chr2-182935297-C-T

Position:

• chr2-182935297-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_013436.5(NCKAP1):​c.2774G>A​(p.Arg925Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCKAP1 NM_013436.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

Genes affected

NCKAP1 (HGNC:7666): (NCK associated protein 1) Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex. [provided by Alliance of Genome Resources, Apr 2022]

NCKAP1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NCKAP1. . Gene score misZ 4.2701 (greater than the threshold 3.09). Trascript score misZ 3.8253 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36664867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.2774G>A	p.Arg925Lys	missense_variant	25/31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.2792G>A	p.Arg931Lys	missense_variant	26/32		NP_995314.1
NCKAP1	XM_006712200.4	c.2786G>A	p.Arg929Lys	missense_variant	26/32		XP_006712263.1
NCKAP1	XM_006712201.4	c.2768G>A	p.Arg923Lys	missense_variant	25/31		XP_006712264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.2774G>A	p.Arg925Lys	missense_variant	25/31	1	NM_013436.5	ENSP00000355348.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.020
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.30	N;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.15
Sift	Benign	0.39	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.30	B;B
Vest4		0.52
MutPred		0.60		Gain of ubiquitination at R925 (P = 0.0539);.;
MVP		0.39
MPC		1.7
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.66

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: chr2-183800025;