5-139848399-A-C

Variant summary

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

The NM_004883.3(NRG2):c.2071T>G(p.Cys691Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000189 in 1,110,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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]

(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=0.37280712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3	c.2071T>G	p.Cys691Gly	missense_variant	10/10	ENST00000361474.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG2	ENST00000361474.6	c.2071T>G	p.Cys691Gly	missense_variant	10/10	1	NM_004883.3	A2
	ENST00000504413.1	n.110A>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000189 AC: 21 AN: 1110584 Hom.: 0 Cov.: 34 AF XY: 0.0000302 AC XY: 16 AN XY: 529660

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: 0.0000212

Gnomad4 OTH exome AF: 0.0000224

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000756

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 18, 2023

The c.2095T>G (p.C699G) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a T to G substitution at nucleotide position 2095, causing the cysteine (C) at amino acid position 699 to be replaced by a glycine (G). 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	0.063
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Benign	0.82
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.96	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.12	T;T;T;T;T;T
Sift4G	Benign	0.074	T;T;T;T;T;T
Polyphen		0.0010, 0.17, 0.11	.;B;B;.;B;B
Vest4		0.20
MutPred		0.36		.;.;Loss of loop (P = 0.0512);.;.;.;
MVP		0.82
MPC		1.1
ClinPred		0.25	T
GERP RS		2.7
Varity_R		0.26
gMVP		0.18

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: rs1299468245; hg19: chr5-139227984;