3-136946173-C-T

Variant names:

• chr3-136946173-C-T
• rs868431322
• NM_001291999.2:c.817C>T

Variant summary

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

The NM_001291999.2(NCK1):​c.817C>T​(p.Leu273Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NCK1 NM_001291999.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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]

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

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]

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=0.09403399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCK1	NM_001291999.2	c.817C>T	p.Leu273Phe	missense_variant	Exon 3 of 4	ENST00000481752.6	NP_001278928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCK1	ENST00000481752.6	c.817C>T	p.Leu273Phe	missense_variant	Exon 3 of 4	5	NM_001291999.2	ENSP00000417273.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000896

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.817C>T (p.L273F) alteration is located in exon 3 (coding exon 2) of the NCK1 gene. This alteration results from a C to T substitution at nucleotide position 817, causing the leucine (L) at amino acid position 273 to be replaced by a phenylalanine (F). 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	0.073
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.69	N;N;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.64	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.11	B;B;.;.
Vest4		0.13
MutPred		0.37		Gain of methylation at K276 (P = 0.1249);Gain of methylation at K276 (P = 0.1249);.;.;
MVP		0.79
MPC		0.39
ClinPred		0.29	T
GERP RS		4.3
Varity_R		0.048
gMVP		0.18

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: rs868431322; hg19: chr3-136665015;