rs104893916

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000112.4(SLC26A2):c.2033G>T(p.Gly678Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G678L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 3.97

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]

SLC26A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000112.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 5-149981626-G-T is Pathogenic according to our data. Variant chr5-149981626-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4 linkuse as main transcript	c.2033G>T	p.Gly678Val	missense_variant	3/3	ENST00000286298.5
SLC26A2	XM_017009191.3 linkuse as main transcript	c.2033G>T	p.Gly678Val	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5 linkuse as main transcript	c.2033G>T	p.Gly678Val	missense_variant	3/3	1	NM_000112.4	P1
SLC26A2	ENST00000503336.1 linkuse as main transcript	c.372+3275G>T		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251126

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727200

show subpopulations

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000770

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple epiphyseal dysplasia type 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Mar 16, 2014

- -

Achondrogenesis, type IB

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

Osteochondrodysplasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 01, 2023

Variant summary: SLC26A2 c.2033G>T (p.Gly678Val) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251126 control chromosomes. c.2033G>T has been reported in the literature as a compound heterozygous genotype with a null allele in at-least one individual affected with Sulfate Transporter-Related Osteochondrodysplasia (example, Karniski_2001 citing Superti-Furga_1996). Multiple publications report experimental evidence evaluating an impact on protein function (example, Karniski_2001, Karniski_2004, Rapp_2019). The most pronounced variant effect results in <10% of normal sulfate transport activity in-vitro when analyzed in mammalian cell system (Karniski_2004) however retained partial function when expressed in Xenopus oocytes (Karniski_2001). Another recent study reported ER retention and degradation by ER-associated degradation (ERAD) (Rapp_2019). The following publications have been ascertained in the context of this evaluation (PMID: 11448940, 15294877, 30462520, 8723100). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Diastrophic dysplasia

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.29

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.84

MVP

0.99

MPC

0.32

ClinPred

1.0

GERP RS

6.0

Varity_R

0.97

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over