5-139848200-C-T

Variant names:

• chr5-139848200-C-T
• rs1412099217
• NM_004883.3:c.2270G>A

Variant summary

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

The NM_004883.3(NRG2):​c.2270G>A​(p.Arg757Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,315,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. R757P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• 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=0.31155866).

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.2270G>A	p.Arg757Gln	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2294G>A	p.Arg765Gln	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2276G>A	p.Arg759Gln	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.2270G>A	p.Arg757Gln	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2276G>A	p.Arg759Gln	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2294G>A	p.Arg765Gln	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.00000669 AC: 1 AN: 149532 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000257 AC: 3 AN: 1165808 Hom.: 0 Cov.: 33 AF XY: 0.00000354 AC XY: 2 AN XY: 565558

African (AFR) AF: 0.00 AC: 0 AN: 22850

American (AMR) AF: 0.00 AC: 0 AN: 9332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15692

East Asian (EAS) AF: 0.00 AC: 0 AN: 25296

South Asian (SAS) AF: 0.0000443 AC: 2 AN: 45118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3182

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 969898

Other (OTH) AF: 0.00 AC: 0 AN: 46918

GnomAD4 genome AF: 0.00000669 AC: 1 AN: 149532 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 72876

African (AFR) AF: 0.00 AC: 0 AN: 41080

American (AMR) AF: 0.00 AC: 0 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66998

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.042
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.45	N
REVEL	Benign	0.12
Sift	Benign	0.068	T
Sift4G	Benign	0.66	T
Polyphen		0.99	D
Vest4		0.16
MutPred		0.44		Loss of methylation at R757 (P = 0.0125)
MVP		0.57
MPC		1.8
ClinPred		0.79	D
GERP RS		2.7
Varity_R		0.11
gMVP		0.30
Mutation Taster		=95/5	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: rs1412099217; hg19: chr5-139227785;