chr1-156814269-T-C

Position:

• chr1-156814269-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003975.4(SH2D2A):​c.334A>G​(p.Lys112Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SH2D2A NM_003975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.187

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13798761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D2A	NM_003975.4	c.334A>G	p.Lys112Glu	missense_variant	4/9	ENST00000368199.8	NP_003966.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D2A	ENST00000368199.8	c.334A>G	p.Lys112Glu	missense_variant	4/9	1	NM_003975.4	ENSP00000357182	P2
SH2D2A	ENST00000392306.2	c.364A>G	p.Lys122Glu	missense_variant	4/9	1		ENSP00000376123
SH2D2A	ENST00000368198.7	c.280A>G	p.Lys94Glu	missense_variant	4/9	1		ENSP00000357181	A2
SH2D2A	ENST00000486350.1	n.401A>G		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.364A>G (p.K122E) alteration is located in exon 4 (coding exon 4) of the SH2D2A gene. This alteration results from a A to G substitution at nucleotide position 364, causing the lysine (K) at amino acid position 122 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	.;D;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Benign	1.1	.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N;D
REVEL	Benign	0.28
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.026, 0.021	.;B;B
Vest4		0.15
MutPred		0.44		.;Loss of ubiquitination at K112 (P = 0.0141);.;
MVP		0.89
MPC		0.39
ClinPred		0.16	T
GERP RS		-0.87
Varity_R		0.14
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156784061;