6-41350708-G-C

Variant summary

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

The NM_004828.4(NCR2):c.675G>C(p.Glu225Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,986 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NCR2 NM_004828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.515

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 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=0.16853759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCR2	NM_004828.4	c.675G>C	p.Glu225Asp	missense_variant	5/5	ENST00000373089.10
NCR2	NM_001199509.2	c.*5G>C		3_prime_UTR_variant	6/6
NCR2	NM_001199510.2	c.*5G>C		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCR2	ENST00000373089.10	c.675G>C	p.Glu225Asp	missense_variant	5/5	1	NM_004828.4	P2
NCR2	ENST00000373083.8	c.*5G>C		3_prime_UTR_variant	6/6	1		A2
NCR2	ENST00000373086.3	c.*5G>C		3_prime_UTR_variant	6/6	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461710 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74456

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: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.00173 AC: 6 AN: 3478

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

Jun 02, 2023

The c.675G>C (p.E225D) 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 675, causing the glutamic acid (E) at amino acid position 225 to be replaced by an aspartic acid (D). 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	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.19
Dann	Benign	0.97
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.044
Sift	Uncertain	0.011	D
Sift4G	Benign	0.49	T
Polyphen		0.99	D
Vest4		0.15
MutPred		0.28		Loss of sheet (P = 0.0817);
MVP		0.41
MPC		0.15
ClinPred		0.25	T
GERP RS		-1.3
Varity_R		0.067
gMVP		0.060

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: rs371979973; hg19: chr6-41318446;