6-41336255-C-T

Position:

• chr6-41336255-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.221C>T​(p.Thr74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 1,614,184 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: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: NCR2 NM_004828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.13

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=0.004593998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCR2	NM_004828.4	c.221C>T	p.Thr74Met	missense_variant	2/5	ENST00000373089.10	NP_004819.2
NCR2	NM_001199509.2	c.221C>T	p.Thr74Met	missense_variant	2/6		NP_001186438.1
NCR2	NM_001199510.2	c.221C>T	p.Thr74Met	missense_variant	2/6		NP_001186439.1
NCR2	XM_017011500.2	c.245C>T	p.Thr82Met	missense_variant	2/5		XP_016866989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCR2	ENST00000373089.10	c.221C>T	p.Thr74Met	missense_variant	2/5	1	NM_004828.4	ENSP00000362181.5
NCR2	ENST00000373086.3	c.221C>T	p.Thr74Met	missense_variant	2/6	1		ENSP00000362178.3
NCR2	ENST00000373083.8	c.221C>T	p.Thr74Met	missense_variant	2/6	1		ENSP00000362175.4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000625 AC: 157 AN: 251400 Hom.: 1 AF XY: 0.000677 AC XY: 92 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000390 AC: 570 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.000395 AC XY: 287 AN XY: 727244

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000749 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000382

EpiControl AF: 0.000593

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

Sep 16, 2021

The c.221C>T (p.T74M) alteration is located in exon 2 (coding exon 2) of the NCR2 gene. This alteration results from a C to T substitution at nucleotide position 221, causing the threonine (T) at amino acid position 74 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.93	P;D;P
Vest4		0.10
MVP		0.64
MPC		0.31
ClinPred		0.083	T
GERP RS		-2.1
Varity_R		0.048
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61733061; hg19: chr6-41303993;