5-139848200-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004883.3(NRG2):​c.2270G>C​(p.Arg757Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R757W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Arg757Pro	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2294G>C	p.Arg765Pro	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2276G>C	p.Arg759Pro	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>C	p.Arg757Pro	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2276G>C	p.Arg759Pro	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2294G>C	p.Arg765Pro	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1165808 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 969898

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

GnomAD4 genome Cov.: 29

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	0.19
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.20
Sift	Uncertain	0.025	D
Sift4G	Benign	0.38	T
Polyphen		1.0	D
Vest4		0.45
MutPred		0.49		Loss of MoRF binding (P = 9e-04)
MVP		0.55
MPC		2.2
ClinPred		0.81	D
GERP RS		2.7
Varity_R		0.40
gMVP		0.41
Mutation Taster		=70/30	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;