5-139848273-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004883.3(NRG2):c.2197T>C(p.Ser733Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,109,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.26459065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3 linkuse as main transcript	c.2197T>C	p.Ser733Pro	missense_variant	10/10	ENST00000361474.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG2	ENST00000361474.6 linkuse as main transcript	c.2197T>C	p.Ser733Pro	missense_variant	10/10	1	NM_004883.3	A2	O14511-1
	ENST00000504413.1 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000167

AC:

AN:

143460

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000757

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

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:

0.000292

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000418

AC:

404

AN:

966230

Hom.:

Cov.:

AF XY:

0.000423

AC XY:

192

AN XY:

453796

show subpopulations

Gnomad4 AFR exome

AF:

0.000105

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:

0.000459

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000167

AC:

AN:

143572

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

AN XY:

69892

show subpopulations

Gnomad4 AFR

AF:

0.0000755

Gnomad4 AMR

AF:

0.000137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000292

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000613

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.2221T>C (p.S741P) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a T to C substitution at nucleotide position 2221, causing the serine (S) at amino acid position 741 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

0.086

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Benign

0.90

Eigen

Benign

-0.031

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.74

T;T;T;T;T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

0.93

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.61

N;N;N;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.23

T;T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.99, 0.99, 0.94, 0.0010

.;D;D;.;P;B

Vest4

0.13

MutPred

0.43

.;.;Loss of phosphorylation at S733 (P = 7e-04);.;.;.;

MVP

0.69

MPC

1.0

ClinPred

0.55

GERP RS

2.1

Varity_R

0.26

gMVP

0.21

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