rs386833492

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000112.4(SLC26A2):​c.-26+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 151,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SLC26A2
NM_000112.4 splice_donor, intron

Scores

1
1
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 2.99
Variant links:
Genes affected
SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-149960981-T-C is Pathogenic according to our data. Variant chr5-149960981-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149960981-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A2NM_000112.4 linkc.-26+2T>C splice_donor_variant, intron_variant Intron 1 of 2 ENST00000286298.5 NP_000103.2 P50443
SLC26A2XM_017009191.3 linkc.-26+2T>C splice_donor_variant, intron_variant Intron 1 of 3 XP_016864680.1 P50443

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A2ENST00000286298.5 linkc.-26+2T>C splice_donor_variant, intron_variant Intron 1 of 2 1 NM_000112.4 ENSP00000286298.4 P50443
SLC26A2ENST00000433184.1 linkc.-306+2T>C splice_donor_variant, intron_variant Intron 1 of 2 4 ENSP00000405496.1 C9JAN6
SLC26A2ENST00000690410.1 linkn.207+2T>C splice_donor_variant, intron_variant Intron 1 of 1

Frequencies

GnomAD3 genomes
AF:
0.000542
AC:
82
AN:
151424
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000485
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00438
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000487
Gnomad OTH
AF:
0.000480
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
302
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
234
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000541
AC:
82
AN:
151542
Hom.:
0
Cov.:
33
AF XY:
0.000648
AC XY:
48
AN XY:
74034
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00438
Gnomad4 NFE
AF:
0.000487
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.000870
Hom.:
0
Bravo
AF:
0.000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Mar 31, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 14, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC26A2: PM3:Very Strong, PM1, PM2, PP4 -

Feb 09, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SLC26A2 c.-26+2T>C variant (rs386833492) is reported as a founder variant in the Finnish population, largely in patients affected with diastrophic dysplasia (Hastbacka 1999). This variant is also reported in the homozygous or compound heterozygous state in patients with atelosteogenesis II, diastrophic dysplasia (DTD), diastrophic dysplasia variant, multiple epiphyseal dysplasia (rMED) as well as in the intermediate phenotype between DTD and rMED (Zechi-Ceide 2013). This variant disrupts the canonical splice donor site of intron 1, and functional assays show that patients homozygous for the c.-26+2T>C variant had approximately 5% of correctly spliced mRNA (Hasbacka 1999). This variant is found in the general population with an overall allele frequency of 0.14% (43/31128 alleles), with an increased frequency in the Finnish population of 0.69% in the Genome Aggregation Database (v2.1.1). Based on available information, this variant is considered to be pathogenic. References: Hastbacka J et al. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet. 1999 Sep;7(6):664-70. PMID: 10482955. Zechi-Ceide RM et al. A compound heterozygote SLC26A2 mutation resulting in robin sequence, mild limbs shortness, accelerated carpal ossification, and multiple epiphysial dysplasia in two Brazilian sisters. A new intermediate phenotype between diastrophic dysplasia and recessive multiple epiphyseal dysplasia. Am J Med Genet A. 2013 Aug;161A(8):2088-94. PMID: 23840040. -

Jul 12, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The mRNA expression assay revealed that homozygous patients have a low but detectable level of correctly spliced mRNA, estimated to be approximately 5% of the wild-type allele (PMID: 10482955); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18708426, 34064542, 33726816, 23840040, 21155763, 30423444, 24598000, 21922596, 21077202, 26147798, 27096365, 28569743, 33728303, 32655299, 34831381, 34627339, 37829280, 37265969, 36660027, 36285626, 35611473, 36651276, 36140680, 34493867, 38459613, 10482955, 20301524) -

Diastrophic dysplasia Pathogenic:4Other:1
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 01, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 26, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Apr 07, 2021
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Achondrogenesis, type IB Pathogenic:3
Dec 26, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 20, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Atelosteogenesis type II Pathogenic:2
Jan 06, 2020
Reproductive Health Research and Development, BGI Genomics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

NG_007147.2(NM_000112.3):c.-26+2T>C in the SLC26A2 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. Makitie O. et al. reported that one patient was homozygous for the Finnish major SLC26A2 mutation IVS1+2T>C, four were compound heterozygotes with this mutation and Arg279Trp and all of them were affected with multiple epiphyseal dysplasia (PMID: 24598000). The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -

Apr 07, 2021
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Multiple epiphyseal dysplasia type 4 Pathogenic:2
Dec 26, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Apr 07, 2021
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:2
Mar 07, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 07, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 1 of the SLC26A2 gene. It does not directly change the encoded amino acid sequence of the SLC26A2 protein. This variant is present in population databases (rs386833492, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with SLC26A2-related diseases in affected families (PMID: 10482955, 21077202, 23840040). It is commonly reported in individuals of Finnish ancestry (PMID: 10482955, 21077202, 23840040). ClinVar contains an entry for this variant (Variation ID: 4097). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

SLC26A2-related disorder Pathogenic:1
Oct 10, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SLC26A2 c.-26+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product.This variant, which has been described as a founder variant in the Finnish population, has been reported in at least six studies and is found in a total of at least 101 probands including 70 in a homozygous state, 17 in a compound heterozygous state, and 14 in a heterozygous state (Hästbacka et al. 1999; Bonafé et al. 2008; Dwyer et al. 2010; Jackson et al. 2012; Zechi-Ceide et al. 2013; Mäkitie et al. 2015). Of the 101 probands, 77 probands were affected by diastrophic dysplasia, six probands with recessively inherited multiple epiphyseal dysplasia, three probands with a phenotype that was intermediate between diastrophic dysplasia and multiple epiphyseal dysplasia, and one proband with atelosteogenesis. No probands were reported with achondrogenesis or sulfate transporter-related osteochondrodysplasia. The c.-26+2T>C variant is present in at least four unaffected parents in a heterozygous state (Bonafé et al. 2008; Dwyer et al. 2010). The variant was absent from 200 control samples and is reported at a frequency of 0.01515 in the Finnish population of the 1000 Genomes Project. RT-PCR assays using skin fibroblasts from probands homozygous for the c.-26+2T>C variant showed a 5% level of wild type mRNA which was correctly spliced (Hästbacka et al. 1999). Based on the collective evidence, the c.-26+2T>C variant is classified as pathogenic for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Feb 19, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: SLC26A2 c.-26+2T>C is located in a canonical splice-site in the 5'UTR and is predicted to affect mRNA splicing, resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. This is supported by at least one publication that reports a near complete loss of properly spliced mRNA from patient fibroblasts (Hastbacka_1999). The variant allele was found at a frequency of 0.0014 in 30678 control chromosomes (gnomAD), which does not exceed the maximal expected frequency for a pathogenic variant in the SLC26A2 gene. The c.-26+2T>C variant has been reported in the literature in numerous individuals affected with Sulfate Transporter-Related Osteochondrodysplasia as a homozygous and compound heterozygous allele, and is referred to in the literature as a founder mutation in the Finnish population (Hastbacka_1999). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, though several submitters prior to 2014 classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

3MC syndrome 2 Pathogenic:1
Dec 26, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000112.3(SLC26A2):c.-26+2T>C is classified as pathogenic in the context of SLC26A2-related disorders. Sources cited for classification include the following: PMID 10482955 and 21077202. Classification of NM_000112.3(SLC26A2):c.-26+2T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
26
DANN
Benign
0.96
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.90
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.90
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833492; hg19: chr5-149340544; API