2-105881657-G-T

Position:

• chr2-105881657-G-T

Variant summary

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

The NM_003581.5(NCK2):​c.556G>T​(p.Ala186Ser) 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. 16/21 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: NCK2 NM_003581.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

Genes affected

NCK2 (HGNC:7665): (NCK adaptor protein 2) This gene encodes a member of the NCK family of adaptor proteins. The protein contains three SH3 domains and one SH2 domain. The protein has no known catalytic function but has been shown to bind and recruit various proteins involved in the regulation of receptor protein tyrosine kinases. It is through these regulatory activities that this protein is believed to be involved in cytoskeletal reorganization. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

(HGNC:):

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=0.068309546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCK2	NM_003581.5	c.556G>T	p.Ala186Ser	missense_variant	4/5	ENST00000233154.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCK2	ENST00000233154.9	c.556G>T	p.Ala186Ser	missense_variant	4/5	5	NM_003581.5	P1
	ENST00000652190.1	n.752-6921C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

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

Oct 03, 2022

The c.556G>T (p.A186S) alteration is located in exon 1 (coding exon 1) of the NCK2 gene. This alteration results from a G to T substitution at nucleotide position 556, causing the alanine (A) at amino acid position 186 to be replaced by a serine (S). 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	0.074
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.076
Sift	Benign	0.14	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MutPred		0.34		Gain of phosphorylation at A186 (P = 0.0148);Gain of phosphorylation at A186 (P = 0.0148);
MVP		0.45
MPC		0.69
ClinPred		0.063	T
GERP RS		1.6
Varity_R		0.025
gMVP		0.22

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: rs755385208; hg19: chr2-106498113;