Variant chr3-136945747-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001291999.2(NCK1):c.391A>G(p.Thr131Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NCK1
NM_001291999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

Variant links:

Genes affected

NCK1 (HGNC:7664): (NCK adaptor protein 1) The protein encoded by this gene is one of the signaling and transforming proteins containing Src homology 2 and 3 (SH2 and SH3) domains. It is located in the cytoplasm and is an adaptor protein involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as RAS. Alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, Jun 2010]

NCK1 links:

NCK1 (HGNC:):

NCK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31656706).

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCK1	NM_001291999.2 linkuse as main transcript	c.391A>G	p.Thr131Ala	missense_variant	3/4	ENST00000481752.6	NP_001278928.1	P16333-1A0A0S2Z4Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCK1	ENST00000481752.6 linkuse as main transcript	c.391A>G	p.Thr131Ala	missense_variant	3/4	5	NM_001291999.2	ENSP00000417273.1		P16333-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251292

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727238

show subpopulations

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.391A>G (p.T131A) alteration is located in exon 3 (coding exon 2) of the NCK1 gene. This alteration results from a A to G substitution at nucleotide position 391, causing the threonine (T) at amino acid position 131 to be replaced by an alanine (A). 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

0.11

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.19

T;T;T;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.66

.;T;T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.32

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.45

N;N;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.073

T;T;T;T;T

Sift4G

Benign

0.37

T;T;T;T;T

Polyphen

0.57

P;P;.;.;.

Vest4

0.40

MutPred

0.61

Gain of ubiquitination at K132 (P = 0.0856);Gain of ubiquitination at K132 (P = 0.0856);Gain of ubiquitination at K132 (P = 0.0856);.;.;

MVP

0.80

MPC

0.40

ClinPred

0.52

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.59

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