5-139848291-G-C

Variant names:

• chr5-139848291-G-C
• rs1280056705
• NM_004883.3:c.2179C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004883.3(NRG2):​c.2179C>G​(p.Pro727Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000101 in 989,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P727S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38582376).

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.2179C>G	p.Pro727Ala	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2203C>G	p.Pro735Ala	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2185C>G	p.Pro729Ala	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.2179C>G	p.Pro727Ala	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2185C>G	p.Pro729Ala	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2203C>G	p.Pro735Ala	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 989646 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 465250

African (AFR) AF: 0.00 AC: 0 AN: 19800

American (AMR) AF: 0.00 AC: 0 AN: 5492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10392

East Asian (EAS) AF: 0.00 AC: 0 AN: 18264

South Asian (SAS) AF: 0.00 AC: 0 AN: 18736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2448

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 861660

Other (OTH) AF: 0.00 AC: 0 AN: 37172

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.097	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.037	D
Polyphen		0.76	P
Vest4		0.17
MutPred		0.37		Loss of glycosylation at P727 (P = 0.0018)
MVP		0.88
MPC		1.7
ClinPred		0.75	D
GERP RS		2.7
Varity_R		0.046
gMVP		0.35
Mutation Taster		=82/18	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: rs1280056705; hg19: chr5-139227876;