rs1057517461

Positions:

• chr5-149978353-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_000112.4(SLC26A2):​c.699+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A2 NM_000112.4 splice_donor
• Scores: Splicing: ADA: 0.9892
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 8.02

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 13 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 5-149978353-T-C is Pathogenic according to our data. Variant chr5-149978353-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 371684.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	c.699+2T>C		splice_donor_variant		ENST00000286298.5
SLC26A2	XM_017009191.3	c.699+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5	c.699+2T>C		splice_donor_variant		1	NM_000112.4	P1
SLC26A2	ENST00000503336.1	c.372+2T>C		splice_donor_variant		3
SLC26A2	ENST00000690410.1	n.933T>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Atelosteogenesis type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 23, 2016

- -

Multiple epiphyseal dysplasia type 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 23, 2016

- -

Achondrogenesis, type IB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 23, 2016

- -

Diastrophic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		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: rs1057517461; hg19: chr5-149357916;