rs951388943

Variant names:

• chr5-139848273-A-G
• rs951388943
• NM_004883.3:c.2197T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-139848273-A-G
• chr5-139848273-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

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. 15/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

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

ENSG00000250692 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26459065).
• BS2: High AC in GnomAd4 at 24 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	NM_004883.3	MANE Select	c.2197T>C	p.Ser733Pro	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2221T>C	p.Ser741Pro	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2203T>C	p.Ser735Pro	missense	Exon 11 of 11	NP_053586.1	O14511-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	ENST00000361474.6	TSL:1 MANE Select	c.2197T>C	p.Ser733Pro	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2203T>C	p.Ser735Pro	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2221T>C	p.Ser741Pro	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.000167 AC: 24 AN: 143460 Hom.: 0 Cov.: 29

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.: 0 Cov.: 30 AF XY: 0.000423 AC XY: 192 AN XY: 453796

African (AFR) AF: 0.000105 AC: 2 AN: 19070

American (AMR) AF: 0.00 AC: 0 AN: 4842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9560

East Asian (EAS) AF: 0.00 AC: 0 AN: 15400

South Asian (SAS) AF: 0.00 AC: 0 AN: 18520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2342

European-Non Finnish (NFE) AF: 0.000459 AC: 389 AN: 847388

Other (OTH) AF: 0.000365 AC: 13 AN: 35584

GnomAD4 genome AF: 0.000167 AC: 24 AN: 143572 Hom.: 0 Cov.: 29 AF XY: 0.000186 AC XY: 13 AN XY: 69892

African (AFR) AF: 0.0000755 AC: 3 AN: 39732

American (AMR) AF: 0.000137 AC: 2 AN: 14628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4744

South Asian (SAS) AF: 0.00 AC: 0 AN: 4622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000292 AC: 19 AN: 65100

Other (OTH) AF: 0.00 AC: 0 AN: 1986

Alfa AF: 0.0000613 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.61	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.13
MutPred		0.43		Loss of phosphorylation at S733 (P = 7e-04)
MVP		0.69
MPC		1.0
ClinPred		0.55	D
GERP RS		2.1
Varity_R		0.26
gMVP		0.21
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs951388943; hg19: chr5-139227858;