1-156815825-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003975.4(SH2D2A):c.123+181C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,396 control chromosomes in the GnomAD database, including 370,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 31223 hom., cov: 31)

Exomes 𝑓: 0.68 ( 338909 hom. )

Consequence

SH2D2A
NM_003975.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.84

Publications

30 publications found

Variant links:

Genes affected

SH2D2A (HGNC:10821): (SH2 domain containing 2A) This gene encodes an adaptor protein thought to function in T-cell signal transduction. A related protein in mouse is responsible for the activation of lymphocyte-specific protein-tyrosine kinase and functions in downstream signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

SH2D2A links:

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

NTRK1 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 1-156815825-G-A is Benign according to our data. Variant chr1-156815825-G-A is described in ClinVar as [Benign]. Clinvar id is 380853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4 link	c.123+181C>T		intron_variant	Intron 2 of 8	ENST00000368199.8	NP_003966.2	Q9NP31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D2A	ENST00000368199.8 link	c.123+181C>T		intron_variant	Intron 2 of 8	1	NM_003975.4	ENSP00000357182.3		Q9NP31-1

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96440

AN:

151824

Hom.:

31197

Cov.:

show subpopulations

Gnomad AFR

AF:

0.505

Gnomad AMI

AF:

0.798

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.819

Gnomad SAS

AF:

0.646

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.677

Gnomad OTH

AF:

0.645

GnomAD2 exomes

AF:

0.674

AC:

169366

AN:

251274

AF XY:

0.676

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.695

Gnomad ASJ exome

AF:

0.698

Gnomad EAS exome

AF:

0.818

Gnomad FIN exome

AF:

0.649

Gnomad NFE exome

AF:

0.677

Gnomad OTH exome

AF:

0.669

GnomAD4 exome

AF:

0.679

AC:

992629

AN:

1461454

Hom.:

338909

Cov.:

AF XY:

0.679

AC XY:

493795

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.491

AC:

16422

AN:

33470

American (AMR)

AF:

0.693

AC:

31008

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.689

AC:

18018

AN:

26134

East Asian (EAS)

AF:

0.817

AC:

32421

AN:

39698

South Asian (SAS)

AF:

0.657

AC:

56669

AN:

86236

European-Finnish (FIN)

AF:

0.650

AC:

34732

AN:

53414

Middle Eastern (MID)

AF:

0.719

AC:

4148

AN:

5766

European-Non Finnish (NFE)

AF:

0.682

AC:

758001

AN:

1111638

Other (OTH)

AF:

0.682

AC:

41210

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

18093

36185

54278

72370

90463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.635

AC:

96511

AN:

151942

Hom.:

31223

Cov.:

AF XY:

0.640

AC XY:

47513

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.506

AC:

20947

AN:

41422

American (AMR)

AF:

0.696

AC:

10621

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2369

AN:

3468

East Asian (EAS)

AF:

0.819

AC:

4213

AN:

5146

South Asian (SAS)

AF:

0.647

AC:

3120

AN:

4822

European-Finnish (FIN)

AF:

0.661

AC:

6988

AN:

10566

Middle Eastern (MID)

AF:

0.714

AC:

210

AN:

294

European-Non Finnish (NFE)

AF:

0.677

AC:

45960

AN:

67934

Other (OTH)

AF:

0.643

AC:

1357

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1732

3464

5196

6928

8660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.665

Hom.:

143032

Bravo

AF:

0.635

Asia WGS

AF:

0.702

AC:

2441

AN:

3478

EpiCase

AF:

0.678

EpiControl

AF:

0.682

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

X-linked lymphoproliferative disease due to SH2D1A deficiency

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary insensitivity to pain with anhidrosis

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.50

(source)

DANN

Benign

0.78

PhyloP100

-1.8

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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1-156815825-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over