5-149960980-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate

The NM_000112.4(SLC26A2):c.-26+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,386 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SLC26A2
NM_000112.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.38

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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 5-149960980-G-A is Pathogenic according to our data. Variant chr5-149960980-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803123.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4 linkuse as main transcript	c.-26+1G>A		splice_donor_variant		ENST00000286298.5
SLC26A2	XM_017009191.3 linkuse as main transcript	c.-26+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
SLC26A2	ENST00000286298.5 linkuse as main transcript	c.-26+1G>A	splice_donor_variant	1	NM_000112.4	P1
SLC26A2	ENST00000433184.1 linkuse as main transcript	c.-306+1G>A	splice_donor_variant	4
SLC26A2	ENST00000690410.1 linkuse as main transcript	n.207+1G>A	splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152268

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152386

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Achondrogenesis, type IB

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 25, 2020

PVS1, PM2 The SLC26A2 c.-26+1G>T variant is a single nucleotide change from a guanine to a thymine at the canonical splice donor site in the 5’UTR. The variant has not been described in the literature to date. A Finnish founder mutation has been described at the adjacent c.-26+2T>C position of the same canonical splice site which is considered pathogenic and for which RNA studies have shown aberrant splicing and reduced mRNA levels (PMID: 10482955; PMID: 11241838). Individuals homozygous for the c.-26+2T>C variant tend to present with a phenotype that is intermediate in severity and diastrophic dysplasia (MIM 222600). Phenotypic differences have been observed between individuals with the same SLC26A2 variant (PMID: 32295296). The c.-26+1G>T variant observed in this patient has not been reported in dbSNP and is absent from population databases (PM2). The variant has not been reported in the ClinVar or HGMD disease databases. Computational splice predictions and its location adjacent to the Finnish founder mutation within the same canonical splice site suggest that the variant may alter splicing and result in severely reduced mRNA levels (PVS1). The variant is located in a predicted region of homozygosity on chromosome 5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Uncertain

0.11

Cadd

Pathogenic

Dann

Uncertain

0.99

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

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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