Genetic Variant NM_004883.3:c.2206A>T (chr5-139848264-T-A) – 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.2206A>T(p.Thr736Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000717 in 1,116,198 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 0.000014 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.33

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=0.2592478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG2	NM_004883.3 link	c.2206A>T	p.Thr736Ser	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.2206A>T	p.Thr736Ser	missense_variant	Exon 10 of 10	1	NM_004883.3	ENSP00000354910.1		O14511-1

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000592

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

971292

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

456334

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000102

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000235

Gnomad4 OTH exome

AF:

0.0000835

GnomAD4 genome

AF:

0.0000138

AC:

AN:

144906

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

70532

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000592

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.18

.;.;T;.;.;.

Eigen

Benign

0.032

Eigen_PC

Benign

0.0036

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.62

T;T;T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.26

T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.93

.;.;L;.;.;.

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.34

N;N;N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.22

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.94, 0.95, 0.97

.;P;P;.;D;P

Vest4

0.18

MutPred

0.42

.;.;Gain of glycosylation at T736 (P = 0.0398);.;.;.;

MVP

0.74

MPC

1.1

ClinPred

0.52

GERP RS

2.7

Varity_R

0.12

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over