rs104893920

chr5-149980866-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000112.4(SLC26A2):c.1273A>G(p.Asn425Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,802 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.27

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 16 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S26A2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000112.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 5-149980866-A-G is Pathogenic according to our data. Variant chr5-149980866-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149980866-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4	c.1273A>G	p.Asn425Asp	missense_variant	3/3	ENST00000286298.5
SLC26A2	XM_017009191.3	c.1273A>G	p.Asn425Asp	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5	c.1273A>G	p.Asn425Asp	missense_variant	3/3	1	NM_000112.4	P1
SLC26A2	ENST00000503336.1	c.372+2515A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461802 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Invitae	Jun 08, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 11448940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A2 protein function. ClinVar contains an entry for this variant (Variation ID: 4093). This missense change has been observed in individual(s) with diastrophic dysplasia (PMID: 8528239, 9342225, 21155763). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 425 of the SLC26A2 protein (p.Asn425Asp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 23, 2021	- -

Achondrogenesis, type IB Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

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	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Loss of helix (P = 0.2022);
MVP		1.0
MPC		0.34
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.98

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

Other links and lift over

dbSNP: rs104893920; hg19: chr5-149360429;