5-139848293-C-G

Variant summary

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

The NM_004883.3(NRG2):c.2177G>C(p.Arg726Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 145,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 29)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24825656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3	c.2177G>C	p.Arg726Pro	missense_variant	10/10	ENST00000361474.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG2	ENST00000361474.6	c.2177G>C	p.Arg726Pro	missense_variant	10/10	1	NM_004883.3	A2
	ENST00000504413.1	n.4C>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 145812 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 145812 Hom.: 0 Cov.: 29 AF XY: 0.0000141 AC XY: 1 AN XY: 70998

Gnomad4 AFR AF: 0.0000494

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Apr 07, 2023

The c.2201G>C (p.R734P) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a G to C substitution at nucleotide position 2201, causing the arginine (R) at amino acid position 734 to be replaced by a proline (P). 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	0.088
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T;T;T;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	1.3	N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.098	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		1.0, 0.0050	.;D;D;.;B;D
Vest4		0.17
MutPred		0.51		.;.;Gain of glycosylation at R726 (P = 7e-04);.;.;.;
MVP		0.57
MPC		2.2
ClinPred		0.54	D
GERP RS		0.076
Varity_R		0.18
gMVP		0.41

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: rs1486387436; hg19: chr5-139227878;