rs991737258

Variant names:

• chr5-139848348-G-C
• rs991737258
• NM_004883.3:c.2122C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004883.3(NRG2):​c.2122C>G​(p.Pro708Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,220,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13344821).
• 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.2122C>G	p.Pro708Ala	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2146C>G	p.Pro716Ala	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2128C>G	p.Pro710Ala	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.2122C>G	p.Pro708Ala	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2128C>G	p.Pro710Ala	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2146C>G	p.Pro716Ala	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 24 AN: 148748 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000553

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000238

Gnomad OTH AF: 0.000970

GnomAD4 exome AF: 0.000192 AC: 206 AN: 1071942 Hom.: 0 Cov.: 34 AF XY: 0.000193 AC XY: 98 AN XY: 507140

African (AFR) AF: 0.0000455 AC: 1 AN: 21968

American (AMR) AF: 0.00 AC: 0 AN: 7574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13380

East Asian (EAS) AF: 0.00 AC: 0 AN: 24328

South Asian (SAS) AF: 0.00 AC: 0 AN: 21452

European-Finnish (FIN) AF: 0.000375 AC: 8 AN: 21330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2832

European-Non Finnish (NFE) AF: 0.000209 AC: 192 AN: 916466

Other (OTH) AF: 0.000117 AC: 5 AN: 42612

GnomAD4 genome AF: 0.000161 AC: 24 AN: 148748 Hom.: 0 Cov.: 29 AF XY: 0.000165 AC XY: 12 AN XY: 72590

African (AFR) AF: 0.0000244 AC: 1 AN: 40958

American (AMR) AF: 0.00 AC: 0 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000553 AC: 5 AN: 9042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000238 AC: 16 AN: 67164

Other (OTH) AF: 0.000970 AC: 2 AN: 2062

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000151

ClinVar

ClinVar submissions as Germline

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	0.072
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.24	N
REVEL	Benign	0.045
Sift	Benign	0.53	T
Sift4G	Benign	0.51	T
Polyphen		0.076	B
Vest4		0.13
MVP		0.38
MPC		0.81
ClinPred		0.22	T
GERP RS		1.7
Varity_R		0.095
gMVP		0.21
Mutation Taster		=87/13	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: rs991737258; hg19: chr5-139227933;