2-182935297-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.36664867).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NCKAP1NM_013436.5 linkc.2774G>A p.Arg925Lys missense_variant Exon 25 of 31 ENST00000361354.9 NP_038464.1 Q9Y2A7-1
NCKAP1NM_205842.3 linkc.2792G>A p.Arg931Lys missense_variant Exon 26 of 32 NP_995314.1 Q9Y2A7-2
NCKAP1XM_006712200.4 linkc.2786G>A p.Arg929Lys missense_variant Exon 26 of 32 XP_006712263.1 A0A994J6K9
NCKAP1XM_006712201.4 linkc.2768G>A p.Arg923Lys missense_variant Exon 25 of 31 XP_006712264.1 A0A994J4I5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NCKAP1ENST00000361354.9 linkc.2774G>A p.Arg925Lys missense_variant Exon 25 of 31 1 NM_013436.5 ENSP00000355348.3 Q9Y2A7-1

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 11, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; API