Genetic Variant NM_004883.3:c.2209T>A (chr5-139848261-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004883.3(NRG2):c.2209T>A(p.Ser737Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,114,668 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20104152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG2	NM_004883.3 link	c.2209T>A	p.Ser737Thr	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.2209T>A	p.Ser737Thr	missense_variant	Exon 10 of 10	1	NM_004883.3	ENSP00000354910.1		O14511-1

Frequencies

GnomAD3 genomes

AF:

0.00000695

AC:

AN:

143978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000103

AC:

AN:

970690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

456108

show subpopulations

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:

0.00000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000695

AC:

AN:

143978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70022

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000153

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.19

.;.;T;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.70

T;T;T;T;T;T

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

.;.;L;.;.;.

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.53

N;N;N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.10

T;T;T;T;T;T

Sift4G

Uncertain

0.045

D;D;D;T;D;D

Polyphen

0.37, 0.42, 0.34

.;B;B;.;B;B

Vest4

0.16

MutPred

0.30

.;.;Gain of catalytic residue at S737 (P = 0.0499);.;.;.;

MVP

0.67

MPC

1.0

ClinPred

0.23

GERP RS

1.4

Varity_R

0.15

gMVP

0.26

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over