6-41350690-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004828.4(NCR2):c.657G>C(p.Trp219Cys) 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. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NCR2 NM_004828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390

Genes affected

NCR2 (HGNC:6732): (natural cytotoxicity triggering receptor 2) Predicted to enable signaling receptor activity. Predicted to be involved in cellular defense response and signal transduction. Predicted to be located in plasma membrane. Predicted to be integral component of plasma membrane. Predicted to be active in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06608158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCR2	NM_004828.4	c.657G>C	p.Trp219Cys	missense_variant	5/5	ENST00000373089.10
NCR2	NM_001199509.2	c.800G>C	p.Gly267Ala	missense_variant	6/6
NCR2	NM_001199510.2	c.764G>C	p.Gly255Ala	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCR2	ENST00000373089.10	c.657G>C	p.Trp219Cys	missense_variant	5/5	1	NM_004828.4	P2
NCR2	ENST00000373086.3	c.800G>C	p.Gly267Ala	missense_variant	6/6	1		A2
NCR2	ENST00000373083.8	c.764G>C	p.Gly255Ala	missense_variant	6/6	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.657G>C (p.W219C) alteration is located in exon 5 (coding exon 5) of the NCR2 gene. This alteration results from a G to C substitution at nucleotide position 657, causing the tryptophan (W) at amino acid position 219 to be replaced by a cysteine (C). 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	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	5.5
Dann	Benign	0.88
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.055
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.25	B;B
Vest4		0.19
MutPred		0.11		.;Gain of catalytic residue at G267 (P = 0.0727);
MVP		0.21
ClinPred		0.35	T
GERP RS		-1.5

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41318428;