Genetic Variant NM_004883.3:c.2186C>A (chr5-139848284-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004883.3(NRG2):c.2186C>A(p.Ala729Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.962

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NRG2 links:

ENSG00000250692 (HGNC:):

ENSG00000250692 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2537119).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004883.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRG2	NM_004883.3	MANE Select	c.2186C>A	p.Ala729Glu	missense	Exon 10 of 10	NP_004874.1	O14511-1
NRG2	NM_013982.3		c.2210C>A	p.Ala737Glu	missense	Exon 11 of 11	NP_053585.1	O14511-3
NRG2	NM_013983.3		c.2192C>A	p.Ala731Glu	missense	Exon 11 of 11	NP_053586.1	O14511-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRG2	ENST00000361474.6	TSL:1 MANE Select	c.2186C>A	p.Ala729Glu	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
NRG2	ENST00000358522.7	TSL:1	c.2192C>A	p.Ala731Glu	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
NRG2	ENST00000289422.11	TSL:5	c.2210C>A	p.Ala737Glu	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

974872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

458028

African (AFR)

AF:

0.00

AC:

AN:

19330

American (AMR)

AF:

0.00

AC:

AN:

5084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9854

East Asian (EAS)

AF:

0.00

AC:

AN:

16586

South Asian (SAS)

AF:

0.00

AC:

AN:

18590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

14344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2360

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

852508

Other (OTH)

AF:

0.00

AC:

AN:

36216

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.18

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.66

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.4

PhyloP100

0.96

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.28

REVEL

Benign

0.13

Sift

Benign

0.28

Sift4G

Benign

0.52

Polyphen

0.63

Vest4

0.16

MutPred

0.31

Gain of solvent accessibility (P = 0.005)

MVP

0.72

MPC

1.2

ClinPred

0.21

GERP RS

1.3

Varity_R

0.059

gMVP

0.36

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over