1-156815825-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.84

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]

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr1-156815825-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SH2D2A	NM_003975.4	c.123+181C>T		intron_variant		ENST00000368199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D2A	ENST00000368199.8	c.123+181C>T		intron_variant		1	NM_003975.4	P2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96440 AN: 151824 Hom.: 31197 Cov.: 31

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

GnomAD3 exomes AF: 0.674 AC: 169366 AN: 251274 Hom.: 57705 AF XY: 0.676 AC XY: 91790 AN XY: 135806

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 SAS exome AF: 0.655

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.: 57 AF XY: 0.679 AC XY: 493795 AN XY: 727032

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.689

Gnomad4 EAS exome AF: 0.817

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.650

Gnomad4 NFE exome AF: 0.682

Gnomad4 OTH exome AF: 0.682

GnomAD4 genome AF: 0.635 AC: 96511 AN: 151942 Hom.: 31223 Cov.: 31 AF XY: 0.640 AC XY: 47513 AN XY: 74258

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.696

Gnomad4 ASJ AF: 0.683

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.647

Gnomad4 FIN AF: 0.661

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.643

Alfa AF: 0.668 Hom.: 70557

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

X-linked lymphoproliferative disease due to SH2D1A deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary insensitivity to pain with anhidrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.50
Dann	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs1800601; hg19: chr1-156785617; COSMIC: COSV63884607; COSMIC: COSV63884607;