6-41342064-C-T

Variant summary

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

The NM_004828.4(NCR2):c.559C>T(p.Pro187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000068 (0 hom.)
• Consequence: NCR2 NM_004828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0700

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=0.03642246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCR2	NM_004828.4	c.559C>T	p.Pro187Ser	missense_variant	4/5	ENST00000373089.10
NCR2	NM_001199509.2	c.595C>T	p.Pro199Ser	missense_variant	4/6
NCR2	NM_001199510.2	c.559C>T	p.Pro187Ser	missense_variant	4/6
NCR2	XM_017011500.2	c.583C>T	p.Pro195Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCR2	ENST00000373089.10	c.559C>T	p.Pro187Ser	missense_variant	4/5	1	NM_004828.4	P2
NCR2	ENST00000373086.3	c.595C>T	p.Pro199Ser	missense_variant	4/6	1		A2
NCR2	ENST00000373083.8	c.559C>T	p.Pro187Ser	missense_variant	4/6	1		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251280 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461630 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727160

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

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

Oct 06, 2021

The c.559C>T (p.P187S) alteration is located in exon 4 (coding exon 4) of the NCR2 gene. This alteration results from a C to T substitution at nucleotide position 559, causing the proline (P) at amino acid position 187 to be replaced by a serine (S). 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	0.091
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.8
Dann	Benign	0.20
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.0030
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.11	B;B;B
Vest4		0.21
MutPred		0.28		Gain of phosphorylation at P187 (P = 0.0537);Gain of phosphorylation at P187 (P = 0.0537);.;
MVP		0.15
MPC		0.13
ClinPred		0.015	T
GERP RS		0.85
Varity_R		0.022
gMVP		0.10

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: rs765378575; hg19: chr6-41309802;