5-149980602-CTTG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000112.4(SLC26A2):​c.1020_1022delTGT​(p.Val341del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.97
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 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000112.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 5-149980602-CTTG-C is Pathogenic according to our data. Variant chr5-149980602-CTTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149980602-CTTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A2NM_000112.4 linkc.1020_1022delTGT p.Val341del disruptive_inframe_deletion Exon 3 of 3 ENST00000286298.5 NP_000103.2 P50443
SLC26A2XM_017009191.3 linkc.1020_1022delTGT p.Val341del disruptive_inframe_deletion Exon 3 of 4 XP_016864680.1 P50443

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A2ENST00000286298.5 linkc.1020_1022delTGT p.Val341del disruptive_inframe_deletion Exon 3 of 3 1 NM_000112.4 ENSP00000286298.4 P50443
SLC26A2ENST00000503336.1 linkc.372+2262_372+2264delTGT intron_variant Intron 1 of 1 3 ENSP00000426053.1 H0YA38

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000119
AC:
30
AN:
251132
Hom.:
0
AF XY:
0.000147
AC XY:
20
AN XY:
135730
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000326
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000664
AC:
97
AN:
1461764
Hom.:
0
AF XY:
0.0000811
AC XY:
59
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000603
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PM4+PM3_VeryStrong+PS3_Supporting -

Jan 26, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant, c.1020_1022del, results in the deletion of 1 amino acid(s) of the SLC26A2 protein (p.Val341del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777472333, gnomAD 0.03%). This variant has been observed in individuals with SLC26A2-related disorders (PMID: 8528239, 9637425, 10482955, 31218223). ClinVar contains an entry for this variant (Variation ID: 65558). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC26A2 function (PMID: 11448940). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3
Oct 18, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SLC26A2 c.1020_1022delTGT; p.Val341del variant (rs121908077) has been described in association with SLC26A2-related chondrodysplasias (Cai 1998, Superti-Furga 1996). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 65558) and is observed in the general population at an overall frequency of 0.01% (31/276822 alleles) in the Genome Aggregation Database. This variant deletes a single valine residue, leaving the rest of the protein product in-frame. Functional characterization of the variant protein demonstrates reduced protein expression and abnormal sulfate transporter activity (Karniski 2001, Karniski 2004, Superti-Furga 1996). Based on available information, this variant is considered pathogenic. References: Cai G et al. Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. Am J Med Genet. 1998 Jun 16;78(1):58-60. Karniski L et al. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. Hum Mol Genet. 2001 Jul 1;10(14):1485-90. Karniski L et al. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004 Oct 1;13(19):2165-71. Superti-Furga et al. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996 Jan;12(1):100-2. -

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

- -

Jul 18, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate abnormal sulfate transporter activity (Superti-Furga et al. 1996; Karniski et al. 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of one amino acid in a non-repeat region; Reported previously as c.1045_1047delGTT or p.Val340del using alternate nomenclature; This variant is associated with the following publications: (PMID: 15294877, 8528239, 20301689, 10482955, 31218223, 11448940, 9637425) -

Achondrogenesis, type IB Pathogenic:2
Jun 16, 1998
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 23, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1850554:Atelosteogenesis type II Pathogenic:1
Nov 03, 2021
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000112.3(SLC26A2):c.1020_1022delTGT(V341del) is an in-frame deletion classified as likely pathogenic in the context of SLC26A2-related disorders. V341del has been observed in cases with relevant disease (PMID: 9637425, 8528239, 10482955). Functional assessments of this variant are available in the literature (PMID: 11448940, 15294877). V341del has been observed in population frequency databases (gnomAD: EAS 0.03%). In summary, NM_000112.3(SLC26A2):c.1020_1022delTGT(V341del) is an in-frame deletion variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Atelosteogenesis type II Pathogenic:1
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Jul 28, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The SLC26A2 c.1020_1022delTGT (p.Val341del) variant involves the deletion of a Valine in the predicted seventh transmembrane domain of the SLC26A2 protein. One in silico tool predicts a damaging outcome for this variant. This variant was found in 17/121404 control chromosomes at a frequency of 0.00014, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC26A2 variant (0.002958). The variant has been reported in multiple affected individuals in the homozygous and compound heterozygous state, and has been shown to result in impaired ability for sulfate uptake in HEK cells (comparable to negative control cells). In these transfected cells, the protein is not detected by either immunoblot analysis or confocal immunofluorescent microscopy, suggesting that this mutation is either poorly expressed or the protein is rapidly degraded in mammalian cells (Karniski_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic, and this variant is considered a common disease variant. Taken together, this variant is classified as pathogenic. -

Diastrophic dysplasia Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs121908077; hg19: chr5-149360165; API