rs1280056705

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-139848291-G-A
• chr5-139848291-G-C

Variant summary

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

The NM_004883.3(NRG2):​c.2179C>T​(p.Pro727Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000081 in 1,136,268 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3343467).
• BS2: High AC in GnomAd4 at 9 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.2179C>T	p.Pro727Ser	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2203C>T	p.Pro735Ser	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2185C>T	p.Pro729Ser	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>T	p.Pro727Ser	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2185C>T	p.Pro729Ser	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2203C>T	p.Pro735Ser	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.0000614 AC: 9 AN: 146622 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000245

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: 0.000121

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000839 AC: 83 AN: 989646 Hom.: 0 Cov.: 32 AF XY: 0.0000795 AC XY: 37 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: 0.0000963 AC: 83 AN: 861660

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

GnomAD4 genome AF: 0.0000614 AC: 9 AN: 146622 Hom.: 0 Cov.: 29 AF XY: 0.0000420 AC XY: 3 AN XY: 71408

African (AFR) AF: 0.0000245 AC: 1 AN: 40734

American (AMR) AF: 0.00 AC: 0 AN: 14784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000121 AC: 8 AN: 66140

Other (OTH) AF: 0.00 AC: 0 AN: 2022

Alfa AF: 0.000142 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	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.055
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.44	T
Polyphen		0.38	B
Vest4		0.12
MutPred		0.38		Gain of phosphorylation at P727 (P = 5e-04)
MVP		0.86
MPC		1.8
ClinPred		0.76	D
GERP RS		2.7
Varity_R		0.062
gMVP		0.44
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: rs1280056705; hg19: chr5-139227876;