rs1800600

Variant names:

• chr1-156815987-G-A
• rs1800600
• NM_003975.4:c.123+19C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-156815987-G-A
• chr1-156815987-G-C
• chr1-156815987-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003975.4(SH2D2A):​c.123+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,609,636 control chromosomes in the GnomAD database, including 373,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32702 hom., cov: 31)
  • Exomes 𝑓: 0.68 (340612 hom.)
• Consequence: SH2D2A NM_003975.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.797
• Publications: 12 publications found

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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-156815987-G-A is Benign according to our data. Variant chr1-156815987-G-A is described in ClinVar as [Benign]. Clinvar id is 667768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.123+19C>T		intron_variant	Intron 2 of 8	ENST00000368199.8	NP_003966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D2A	ENST00000368199.8	c.123+19C>T		intron_variant	Intron 2 of 8	1	NM_003975.4	ENSP00000357182.3

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99054 AN: 151310 Hom.: 32670 Cov.: 31

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.705

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.659

GnomAD2 exomes AF: 0.676 AC: 167391 AN: 247594 AF XY: 0.676

Gnomad AFR exome AF: 0.565

Gnomad AMR exome AF: 0.693

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.673

Gnomad OTH exome AF: 0.670

GnomAD4 exome AF: 0.682 AC: 994688 AN: 1458206 Hom.: 340612 Cov.: 42 AF XY: 0.682 AC XY: 494642 AN XY: 725294

African (AFR) AF: 0.565 AC: 18895 AN: 33426

American (AMR) AF: 0.696 AC: 30914 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 17965 AN: 26062

East Asian (EAS) AF: 0.817 AC: 32389 AN: 39642

South Asian (SAS) AF: 0.662 AC: 56899 AN: 85986

European-Finnish (FIN) AF: 0.651 AC: 34696 AN: 53298

Middle Eastern (MID) AF: 0.723 AC: 4168 AN: 5764

European-Non Finnish (NFE) AF: 0.683 AC: 757301 AN: 1109348

Other (OTH) AF: 0.688 AC: 41461 AN: 60284

GnomAD4 genome AF: 0.655 AC: 99137 AN: 151430 Hom.: 32702 Cov.: 31 AF XY: 0.658 AC XY: 48687 AN XY: 73954

African (AFR) AF: 0.575 AC: 23750 AN: 41308

American (AMR) AF: 0.700 AC: 10666 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2352 AN: 3452

East Asian (EAS) AF: 0.817 AC: 4167 AN: 5098

South Asian (SAS) AF: 0.654 AC: 3153 AN: 4820

European-Finnish (FIN) AF: 0.660 AC: 6957 AN: 10536

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.676 AC: 45787 AN: 67684

Other (OTH) AF: 0.657 AC: 1387 AN: 2112

Alfa AF: 0.642 Hom.: 13681

Bravo AF: 0.658

Asia WGS AF: 0.708 AC: 2462 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.45
DANN	Benign	0.65
PhyloP100		-0.80
PromoterAI		-0.0048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800600; hg19: chr1-156785779;