chr1-156815979-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.31
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]
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]

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ACMG classification

Classification made for transcript

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
SH2D2ANM_003975.4 linkuse as main transcriptc.123+27T>C intron_variant ENST00000368199.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH2D2AENST00000368199.8 linkuse as main transcriptc.123+27T>C intron_variant 1 NM_003975.4 P2Q9NP31-1

Frequencies

GnomAD3 genomes
AF:
0.598
AC:
90538
AN:
151320
Hom.:
27774
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 08, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 14, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7546838; hg19: chr1-156785771; COSMIC: COSV63884348; COSMIC: COSV63884348; API