Variant 5-139848380-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004883.3(NRG2):c.2090T>C(p.Leu697Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000585 in 1,247,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000046 ( 1 hom. )

Consequence

NRG2
NM_004883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.818

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=0.14813513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG2	NM_004883.3 link	c.2090T>C	p.Leu697Pro	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.2090T>C	p.Leu697Pro	missense_variant	Exon 10 of 10	1	NM_004883.3	ENSP00000354910.1		O14511-1

Frequencies

GnomAD3 genomes

AF:

0.000148

AC:

AN:

148248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000369

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

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:

0.0000747

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000464

AC:

AN:

1099392

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

522882

show subpopulations

Gnomad4 AFR exome

AF:

0.000224

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000397

Gnomad4 SAS exome

AF:

0.0000399

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000353

Gnomad4 OTH exome

AF:

0.000227

GnomAD4 genome

AF:

0.000148

AC:

AN:

148352

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

72518

show subpopulations

Gnomad4 AFR

AF:

0.000368

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000747

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000162

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2114T>C (p.L705P) 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 2114, causing the leucine (L) at amino acid position 705 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

0.099

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;.;T;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.77

T;T;T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;.;L;.;.;.

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.35

N;N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.16

T;T;T;T;T;T

Sift4G

Benign

0.21

T;T;T;T;T;T

Polyphen

0.029, 0.036, 0.012, 0.0070

.;B;B;.;B;B

Vest4

0.22

MVP

0.48

MPC

1.3

ClinPred

0.17

GERP RS

2.7

Varity_R

0.23

gMVP

0.28

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