Variant 2-182928858-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_013436.5(NCKAP1):c.2995C>T(p.Leu999Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.77

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]

NCKAP1 links:

NCKAP1 (HGNC:):

NCKAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCKAP1	NM_013436.5 linkuse as main transcript	c.2995C>T	p.Leu999Phe	missense_variant	28/31	ENST00000361354.9	NP_038464.1	Q9Y2A7-1
NCKAP1	NM_205842.3 linkuse as main transcript	c.3013C>T	p.Leu1005Phe	missense_variant	29/32		NP_995314.1	Q9Y2A7-2
NCKAP1	XM_006712200.4 linkuse as main transcript	c.3007C>T	p.Leu1003Phe	missense_variant	29/32		XP_006712263.1	A0A994J6K9
NCKAP1	XM_006712201.4 linkuse as main transcript	c.2989C>T	p.Leu997Phe	missense_variant	28/31		XP_006712264.1	A0A994J4I5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9 linkuse as main transcript	c.2995C>T	p.Leu999Phe	missense_variant	28/31	1	NM_013436.5	ENSP00000355348.3		Q9Y2A7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250090

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2024

In silico analysis supports that this missense variant has a deleterious effect on 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

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.9

L;.

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.058

T;T

Polyphen

0.58

P;P

Vest4

0.76

MutPred

0.83

Loss of helix (P = 0.0376);.;

MVP

0.47

MPC

1.4

ClinPred

0.92

GERP RS

5.5

Varity_R

0.66

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over