5-149960981-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000112.4(SLC26A2):c.-26+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 151,542 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC26A2
NM_000112.4 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 2.99

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

achondrogenesis type IB
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, Orphanet
atelosteogenesis type II
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet
diastrophic dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
multiple epiphyseal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
multiple epiphyseal dysplasia type 4
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
SLC26A2-related skeletal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
skeletal dysplasia
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

SLC26A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant 5-149960981-T-C is Pathogenic according to our data. Variant chr5-149960981-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000112.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A2	NM_000112.4	MANE Select	c.-26+2T>C		splice_donor intron	N/A	NP_000103.2	P50443

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC26A2	ENST00000286298.5	TSL:1 MANE Select	c.-26+2T>C	splice_donor intron	N/A	ENSP00000286298.4	P50443
SLC26A2	ENST00000862082.1		c.-683T>C	5_prime_UTR	Exon 1 of 3	ENSP00000532141.1
SLC26A2	ENST00000862081.1		c.-196+2T>C	splice_donor intron	N/A	ENSP00000532140.1

Frequencies

GnomAD3 genomes

AF:

0.000542

AC:

AN:

151424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

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:

0.00438

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000487

Gnomad OTH

AF:

0.000480

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

234

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

240

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.000541

AC:

AN:

151542

Hom.:

Cov.:

AF XY:

0.000648

AC XY:

AN XY:

74034

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41320

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4766

European-Finnish (FIN)

AF:

0.00438

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000487

AC:

AN:

67812

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000295

Hom.:

Bravo

AF:

0.000151

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Diastrophic dysplasia (5)

Achondrogenesis, type IB (3)

Atelosteogenesis type II (2)

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II (2)

Multiple epiphyseal dysplasia type 4 (2)

3MC syndrome 2 (1)

SLC26A2-related disorder (1)

Sulfate transporter-related osteochondrodysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Benign

0.96

PhyloP100

3.0

PromoterAI

-0.58

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over