chr19-54906678-G-C

Position:

• chr19-54906678-G-C

Variant summary

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

The NM_004829.7(NCR1):​c.226G>C​(p.Glu76Gln) 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. 14/19 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: NCR1 NM_004829.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.589

Genes affected

NCR1 (HGNC:6731): (natural cytotoxicity triggering receptor 1) Predicted to be involved in cellular defense response; regulation of natural killer cell mediated cytotoxicity; and signal transduction. Predicted to act upstream of or within defense response to virus and detection of virus. Predicted to be located in cell surface. Predicted to be part of SWI/SNF complex. Predicted to be active in plasma membrane. Biomarker of acquired immunodeficiency syndrome; anogenital venereal wart; hepatitis C; and lymphoproliferative syndrome. [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=0.11561492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCR1	NM_004829.7	c.226G>C	p.Glu76Gln	missense_variant	3/7	ENST00000291890.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCR1	ENST00000291890.9	c.226G>C	p.Glu76Gln	missense_variant	3/7	5	NM_004829.7	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000577 AC: 2 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

Jan 09, 2024

The c.226G>C (p.E76Q) alteration is located in exon 3 (coding exon 3) of the NCR1 gene. This alteration results from a G to C substitution at nucleotide position 226, causing the glutamic acid (E) at amino acid position 76 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.41
DANN	Benign	0.85
DEOGEN2	Benign	0.0079	.;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.037	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;.;.;N
REVEL	Benign	0.037
Sift	Benign	0.047	D;.;.;D
Sift4G	Benign	0.31	T;T;T;T
Vest4		0.15
MutPred		0.33		Loss of ubiquitination at K73 (P = 0.0374);.;Loss of ubiquitination at K73 (P = 0.0374);Loss of ubiquitination at K73 (P = 0.0374);
MVP		0.29
MPC		0.12
ClinPred		0.13	T
GERP RS		0.052
gMVP		0.16

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: rs375177680; hg19: chr19-55418036;