5-139848194-G-T

Variant names:

• chr5-139848194-G-T
• rs1387846958
• NM_004883.3:c.2276C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004883.3(NRG2):​c.2276C>A​(p.Ala759Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000839 in 1,191,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04

Genes affected

NRG2 (HGNC:7998): (neuregulin 2) This gene encodes a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ERBB family of receptors, this protein induces the growth and differentiation of epithelial, neuronal, glial, and other types of cells. The gene consists of 12 exons and the genomic structure is similar to that of neuregulin 1, another member of the neuregulin family of ligands. The products of these genes mediate distinct biological processes by acting at different sites in tissues and eliciting different biological responses in cells. This gene is located close to the region for demyelinating Charcot-Marie-Tooth disease locus, but is not responsible for this disease. Alternative transcript variants encoding distinct isoforms have been described. [provided by RefSeq, May 2010]

ENSG00000250692 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3159952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG2	NM_004883.3	c.2276C>A	p.Ala759Glu	missense_variant	Exon 10 of 10	ENST00000361474.6	NP_004874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG2	ENST00000361474.6	c.2276C>A	p.Ala759Glu	missense_variant	Exon 10 of 10	1	NM_004883.3	ENSP00000354910.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1191928 Hom.: 0 Cov.: 33 AF XY: 0.00000172 AC XY: 1 AN XY: 580578

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: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;T;.;.;.
Eigen	Benign	0.082
Eigen_PC	Benign	-0.0072
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;T;T;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	.;.;L;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.040	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.088	T;T;T;T;T;T
Sift4G	Uncertain	0.019	D;D;D;T;D;D
Polyphen		0.94, 0.95, 0.87	.;P;P;.;P;P
Vest4		0.15
MutPred		0.41		.;.;Gain of solvent accessibility (P = 0.0145);.;.;.;
MVP		0.32
MPC		1.7
ClinPred		0.73	D
GERP RS		1.8
Varity_R		0.23
gMVP		0.36

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: rs1387846958; hg19: chr5-139227779;