Variant 2-182925715-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_013436.5(NCKAP1):c.3374C>T(p.Thr1125Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000147 in 1,554,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NCKAP1
NM_013436.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, NCKAP1

BP4

Computational evidence support a benign effect (MetaRNN=0.07362595).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NCKAP1	NM_013436.5 linkuse as main transcript	c.3374C>T	p.Thr1125Ile	missense_variant	31/31	ENST00000361354.9
NCKAP1	NM_205842.3 linkuse as main transcript	c.3392C>T	p.Thr1131Ile	missense_variant	32/32
NCKAP1	XM_006712200.4 linkuse as main transcript	c.3386C>T	p.Thr1129Ile	missense_variant	32/32
NCKAP1	XM_006712201.4 linkuse as main transcript	c.3368C>T	p.Thr1123Ile	missense_variant	31/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCKAP1	ENST00000361354.9 linkuse as main transcript	c.3374C>T	p.Thr1125Ile	missense_variant	31/31	1	NM_013436.5	P4	Q9Y2A7-1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

209516

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

114220

show subpopulations

Gnomad AFR exome

AF:

0.0000734

Gnomad AMR exome

AF:

0.0000836

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

214

AN:

1402688

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

AN XY:

697832

show subpopulations

Gnomad4 AFR exome

AF:

0.000133

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.0000409

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000762

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.0000691

GnomAD4 genome

AF:

0.0000987

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.3392C>T (p.T1131I) alteration is located in exon 32 (coding exon 32) of the NCKAP1 gene. This alteration results from a C to T substitution at nucleotide position 3392, causing the threonine (T) at amino acid position 1131 to be replaced by an isoleucine (I). 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

0.097

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0052

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.048

Sift

Benign

0.18

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.010

B;B

Vest4

0.12

MVP

0.13

MPC

1.3

ClinPred

0.059

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.092

gMVP

0.23

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