6-41336401-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004828.4(NCR2):c.367G>A(p.Val123Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,668 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (31 hom.)
• Consequence: NCR2 NM_004828.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.25

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031606555).
• BP6: Variant 6-41336401-G-A is Benign according to our data. Variant chr6-41336401-G-A is described in ClinVar as [Benign]. Clinvar id is 791266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00159 (2318/1461424) while in subpopulation AMR AF= 0.024 (1074/44720). AF 95% confidence interval is 0.0228. There are 31 homozygotes in gnomad4_exome. There are 990 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCR2	NM_004828.4	c.367G>A	p.Val123Ile	missense_variant	2/5	ENST00000373089.10
NCR2	NM_001199509.2	c.367G>A	p.Val123Ile	missense_variant	2/6
NCR2	NM_001199510.2	c.367G>A	p.Val123Ile	missense_variant	2/6
NCR2	XM_017011500.2	c.391G>A	p.Val131Ile	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCR2	ENST00000373089.10	c.367G>A	p.Val123Ile	missense_variant	2/5	1	NM_004828.4	P2
NCR2	ENST00000373086.3	c.367G>A	p.Val123Ile	missense_variant	2/6	1		A2
NCR2	ENST00000373083.8	c.367G>A	p.Val123Ile	missense_variant	2/6	1		A2

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00578 AC: 1453 AN: 251206 Hom.: 26 AF XY: 0.00438 AC XY: 595 AN XY: 135770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00185

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00159 AC: 2318 AN: 1461424 Hom.: 31 Cov.: 34 AF XY: 0.00136 AC XY: 990 AN XY: 726962

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00280

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152244 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74446

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.00220

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00439 AC: 533

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.037
Dann	Benign	0.45
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.40	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.32	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.095	B;B;B
Vest4		0.028
MVP		0.26
MPC		0.093
ClinPred		0.016	T
GERP RS		-8.3
Varity_R		0.047
gMVP		0.14

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: rs147357473; hg19: chr6-41304139; COSMIC: COSV100897206;