Variant 5-139848349-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004883.3(NRG2):c.2121C>G(p.Ile707Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,220,662 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000061 ( 1 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.35

Variant links:

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]

NRG2 links:

ENSG00000250692 (HGNC:):

ENSG00000250692 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
NRG2	NM_004883.3 link	c.2121C>G	p.Ile707Met	missense_variant	Exon 10 of 10	ENST00000361474.6	NP_004874.1	O14511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG2	ENST00000361474.6 link	c.2121C>G	p.Ile707Met	missense_variant	Exon 10 of 10	1	NM_004883.3	ENSP00000354910.1		O14511-1

Frequencies

GnomAD3 genomes

AF:

0.0000672

AC:

AN:

148726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

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:

0.0000894

Gnomad OTH

AF:

0.000484

GnomAD4 exome

AF:

0.0000606

AC:

AN:

1071936

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

507126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000396

Gnomad4 ASJ exome

AF:

0.0000747

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000546

Gnomad4 OTH exome

AF:

0.000211

GnomAD4 genome

AF:

0.0000672

AC:

AN:

148726

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

72580

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000201

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000894

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2145C>G (p.I715M) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a C to G substitution at nucleotide position 2145, causing the isoleucine (I) at amino acid position 715 to be replaced by a methionine (M). 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

0.21

BayesDel_addAF

Benign

-0.0068

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;T;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.2

.;.;M;.;.;.

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Benign

0.11

T;T;T;D;T;T

Polyphen

0.99, 1.0, 1.0

.;D;D;.;D;D

Vest4

0.36

MutPred

0.59

.;.;Loss of stability (P = 0.189);.;.;.;

MVP

0.57

MPC

1.9

ClinPred

0.91

GERP RS

2.7

Varity_R

0.57

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over