1-156815979-A-G

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+27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,608,350 control chromosomes in the GnomAD database, including 335,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27797 hom., cov: 32)
  • Exomes 𝑓: 0.65 (307322 hom.)
• Consequence: SH2D2A NM_003975.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31

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=-0.86).
• BP6: Variant 1-156815979-A-G is Benign according to our data. Variant chr1-156815979-A-G is described in ClinVar as [Benign]. Clinvar id is 667767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D2A	NM_003975.4	c.123+27T>C		intron_variant		ENST00000368199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D2A	ENST00000368199.8	c.123+27T>C		intron_variant		1	NM_003975.4	P2

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90538 AN: 151320 Hom.: 27774 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.638

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.606

GnomAD3 exomes AF: 0.641 AC: 157680 AN: 246056 Hom.: 50693 AF XY: 0.643 AC XY: 85527 AN XY: 133012

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.647 AC: 943044 AN: 1456910 Hom.: 307322 Cov.: 39 AF XY: 0.648 AC XY: 469662 AN XY: 724586

Gnomad4 AFR exome AF: 0.434

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.590

Gnomad4 EAS exome AF: 0.817

Gnomad4 SAS exome AF: 0.652

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.645

GnomAD4 genome AF: 0.598 AC: 90607 AN: 151440 Hom.: 27797 Cov.: 32 AF XY: 0.603 AC XY: 44603 AN XY: 73952

Gnomad4 AFR AF: 0.455

Gnomad4 AMR AF: 0.659

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.648

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.642

Gnomad4 OTH AF: 0.605

Alfa AF: 0.595 Hom.: 5292

Bravo AF: 0.597

Asia WGS AF: 0.694 AC: 2413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 08, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.31
Dann	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7546838; hg19: chr1-156785771; COSMIC: COSV63884348; COSMIC: COSV63884348;