5-139848200-C-G

Variant summary

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

The NM_004883.3(NRG2):c.2270G>C(p.Arg757Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R757W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3	c.2270G>C	p.Arg757Pro	missense_variant	10/10	ENST00000361474.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG2	ENST00000361474.6	c.2270G>C	p.Arg757Pro	missense_variant	10/10	1	NM_004883.3	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1165808 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 565558

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Jun 22, 2023

The c.2294G>C (p.R765P) 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 2294, causing the arginine (R) at amino acid position 765 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	0.19
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	D;T;T;D;D;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.020	N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.025	D;D;D;D;D;D
Sift4G	Benign	0.38	T;T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;.;D;D
Vest4		0.45
MutPred		0.49		.;.;Loss of MoRF binding (P = 9e-04);.;.;.;
MVP		0.55
MPC		2.2
ClinPred		0.81	D
GERP RS		2.7
Varity_R		0.40
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-139227785;