1-156807267-C-G

Variant names:

• chr1-156807267-C-G
• rs202237236
• NM_003975.4:c.1081G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_003975.4(SH2D2A):​c.1081G>C​(p.Ala361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A361T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2D2A NM_003975.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.169
• Publications: 4 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048122466).
• BP6: Variant 1-156807267-C-G is Benign according to our data. Variant chr1-156807267-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2471514.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.1081G>C	p.Ala361Pro	missense_variant	Exon 8 of 9	ENST00000368199.8	NP_003966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D2A	ENST00000368199.8	c.1081G>C	p.Ala361Pro	missense_variant	Exon 8 of 9	1	NM_003975.4	ENSP00000357182.3
SH2D2A	ENST00000392306.2	c.1111G>C	p.Ala371Pro	missense_variant	Exon 8 of 9	1		ENSP00000376123.2
SH2D2A	ENST00000368198.8	c.1027G>C	p.Ala343Pro	missense_variant	Exon 8 of 9	1		ENSP00000357181.3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 7 AN: 53190 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000557

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000133 AC: 19 AN: 142480 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.000659

Gnomad NFE exome AF: 0.0000395

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00239 AC: 481 AN: 200870 Hom.: 0 Cov.: 0 AF XY: 0.00243 AC XY: 268 AN XY: 110426

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000948 AC: 6 AN: 6330

American (AMR) AF: 0.00156 AC: 22 AN: 14070

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 9 AN: 5850

East Asian (EAS) AF: 0.00112 AC: 9 AN: 8018

South Asian (SAS) AF: 0.00371 AC: 85 AN: 22884

European-Finnish (FIN) AF: 0.00373 AC: 43 AN: 11528

Middle Eastern (MID) AF: 0.00175 AC: 2 AN: 1142

European-Non Finnish (NFE) AF: 0.00231 AC: 283 AN: 122440

Other (OTH) AF: 0.00256 AC: 22 AN: 8608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000132 AC: 7 AN: 53220 Hom.: 0 Cov.: 0 AF XY: 0.000118 AC XY: 3 AN XY: 25496

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000225 AC: 3 AN: 13356

American (AMR) AF: 0.00 AC: 0 AN: 3820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1514

East Asian (EAS) AF: 0.00 AC: 0 AN: 2338

South Asian (SAS) AF: 0.000557 AC: 1 AN: 1794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.000109 AC: 3 AN: 27506

Other (OTH) AF: 0.00 AC: 0 AN: 674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000192 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 02, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.4
DANN	Benign	0.96
DEOGEN2	Benign	0.23	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.90	.;N;.
PhyloP100		-0.17
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.060	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0, 0.0010	.;B;B
Vest4		0.097
MutPred		0.16		.;Gain of glycosylation at A361 (P = 0.0021);.;
MVP		0.56
MPC		0.33
ClinPred		0.033	T
GERP RS		0.46
Varity_R		0.067
gMVP		0.033
Mutation Taster		=96/4	polymorphism

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: rs202237236; hg19: chr1-156777059; COSMIC: COSV63884731; COSMIC: COSV63884731;