Genetic Variant NM_001291999.2:c.999A>C (chr3-136948318-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001291999.2(NCK1):c.999A>C(p.Gln333His) variant causes a missense change involving the alteration of a non-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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

NCK1
NM_001291999.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

Publications

0 publications found

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:

IL20RB (HGNC:6004): (interleukin 20 receptor subunit beta) IL20RB and IL20RA (MIM 605620) form a heterodimeric receptor for interleukin-20 (IL20; MIM 605619) (Blumberg et al., 2001 [PubMed 11163236]).[supplied by OMIM, Feb 2009]

IL20RB links:

IL20RB-AS1 (HGNC:40298): (IL20RB antisense RNA 1)

IL20RB-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34195143).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291999.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCK1	NM_001291999.2	MANE Select	c.999A>C	p.Gln333His	missense	Exon 4 of 4	NP_001278928.1	P16333-1
NCK1	NM_006153.6		c.999A>C	p.Gln333His	missense	Exon 4 of 4	NP_006144.1	P16333-1
NCK1	NM_001190796.3		c.807A>C	p.Gln269His	missense	Exon 3 of 3	NP_001177725.1	P16333-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCK1	ENST00000481752.6	TSL:5 MANE Select	c.999A>C	p.Gln333His	missense	Exon 4 of 4	ENSP00000417273.1	P16333-1
NCK1	ENST00000288986.6	TSL:1	c.999A>C	p.Gln333His	missense	Exon 4 of 4	ENSP00000288986.2	P16333-1
NCK1	ENST00000951211.1		c.1182A>C	p.Gln394His	missense	Exon 5 of 5	ENSP00000621270.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.31

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.055

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.58

PhyloP100

1.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.39

Sift

Benign

0.44

Sift4G

Benign

0.86

Polyphen

0.011

Vest4

0.56

MutPred

0.62

Loss of MoRF binding (P = 0.0994)

MVP

0.71

MPC

1.1

ClinPred

0.64

GERP RS

-3.0

Varity_R

0.33

gMVP

0.58

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over