rs386833492

chr5-149960981-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000112.4(SLC26A2):c.-26+2T>C variant causes a splice donor 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
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09954955 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
SLC26A2	NM_000112.4	c.-26+2T>C		splice_donor_variant		ENST00000286298.5
SLC26A2	XM_017009191.3	c.-26+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5	c.-26+2T>C		splice_donor_variant		1	NM_000112.4	P1
SLC26A2	ENST00000433184.1	c.-306+2T>C		splice_donor_variant		4
SLC26A2	ENST00000690410.1	n.207+2T>C		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000542 AC: 82 AN: 151424 Hom.: 0 Cov.: 33

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

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:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diastrophic dysplasia Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2021	- -

Achondrogenesis, type IB Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SLC26A2: PM3:Very Strong, PM1, PM2, PP4 -

Atelosteogenesis type II Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2021	- -

Multiple epiphyseal dysplasia type 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	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. -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	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

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 10, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 19, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 26, 2019

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

Other links and lift over

dbSNP: rs386833492; hg19: chr5-149340544;