chr5-139848375-T-C

Variant names:

• chr5-139848375-T-C
• rs1264856265
• NM_004883.3:c.2095A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004883.3(NRG2):​c.2095A>G​(p.Ser699Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,243,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 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.2095A>G	p.Ser699Gly	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2119A>G	p.Ser707Gly	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2101A>G	p.Ser701Gly	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.2095A>G	p.Ser699Gly	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2101A>G	p.Ser701Gly	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2119A>G	p.Ser707Gly	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148188 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000913 AC: 10 AN: 1095026 Hom.: 0 Cov.: 34 AF XY: 0.00000961 AC XY: 5 AN XY: 520342

African (AFR) AF: 0.00 AC: 0 AN: 22288

American (AMR) AF: 0.00 AC: 0 AN: 7862

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 4 AN: 13898

East Asian (EAS) AF: 0.00 AC: 0 AN: 25112

South Asian (SAS) AF: 0.00 AC: 0 AN: 24100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2942

European-Non Finnish (NFE) AF: 0.00000322 AC: 3 AN: 932512

Other (OTH) AF: 0.0000684 AC: 3 AN: 43876

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148188 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 72336

African (AFR) AF: 0.00 AC: 0 AN: 40698

American (AMR) AF: 0.00 AC: 0 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9136

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66964

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.30
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.59		Loss of phosphorylation at S699 (P = 0.0308)
MVP		0.56
MPC		1.8
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.76
gMVP		0.42
Mutation Taster		=58/42	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: rs1264856265; hg19: chr5-139227960;