Variant chr5-139848069-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004883.3(NRG2):c.2401G>T(p.Ala801Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,499,318 control chromosomes in the GnomAD database, including 6 homozygotes. 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 0.0014 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0026 ( 6 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01815033).

BS2

High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG2	NM_004883.3 linkuse as main transcript	c.2401G>T	p.Ala801Ser	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.2401G>T	p.Ala801Ser	missense_variant	10/10	1	NM_004883.3	A2	O14511-1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

206

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000382

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00132

AC:

124

AN:

94118

Hom.:

AF XY:

0.00128

AC XY:

AN XY:

53050

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000687

Gnomad ASJ exome

AF:

0.000722

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000822

Gnomad FIN exome

AF:

0.000152

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00251

GnomAD4 exome

AF:

0.00262

AC:

3533

AN:

1347406

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1680

AN XY:

664616

show subpopulations

Gnomad4 AFR exome

AF:

0.000439

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000292

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000799

Gnomad4 FIN exome

AF:

0.000360

Gnomad4 NFE exome

AF:

0.00305

Gnomad4 OTH exome

AF:

0.00291

GnomAD4 genome

AF:

0.00136

AC:

206

AN:

151912

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000382

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00164

ExAC

AF:

0.000692

AC:

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 13, 2021

The c.2425G>T (p.A809S) alteration is located in exon 11 (coding exon 11) of the NRG2 gene. This alteration results from a G to T substitution at nucleotide position 2425, causing the alanine (A) at amino acid position 809 to be replaced by a serine (S). 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

0.066

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.19

.;.;T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

T;T;T;T;T;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;L;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.050

N;N;N;N;N;N

REVEL

Benign

0.054

Sift

Benign

0.22

T;T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T

Polyphen

0.010, 0.022, 0.018, 0.37

.;B;B;.;B;B

Vest4

0.059

MVP

0.39

MPC

0.74

ClinPred

0.024

GERP RS

1.4

Varity_R

0.094

gMVP

0.33

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