2-182925706-G-A

Variant names:

• chr2-182925706-G-A
• rs1696629722
• NM_013436.5:c.3383C>T

Variant summary

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

The NM_013436.5(NCKAP1):​c.3383C>T​(p.Ala1128Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCKAP1 NM_013436.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

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]

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=0.18191114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.3383C>T	p.Ala1128Val	missense_variant	Exon 31 of 31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.3401C>T	p.Ala1134Val	missense_variant	Exon 32 of 32		NP_995314.1
NCKAP1	XM_006712200.4	c.3395C>T	p.Ala1132Val	missense_variant	Exon 32 of 32		XP_006712263.1
NCKAP1	XM_006712201.4	c.3377C>T	p.Ala1126Val	missense_variant	Exon 31 of 31		XP_006712264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.3383C>T	p.Ala1128Val	missense_variant	Exon 31 of 31	1	NM_013436.5	ENSP00000355348.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.25e-7 AC: 1 AN: 1379608 Hom.: 0 Cov.: 24 AF XY: 0.00000146 AC XY: 1 AN XY: 686390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.37e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 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	0.081
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.063
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D;D
Polyphen		0.0	B;B
Vest4		0.55
MutPred		0.22		Loss of loop (P = 0.0986);.;
MVP		0.14
MPC		1.2
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.40

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: rs1696629722; hg19: chr2-183790434;