chr5-139880843-T-C

Variant names:

• chr5-139880843-T-C
• rs889022
• NM_004883.3:c.991+13A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004883.3(NRG2):​c.991+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,609,466 control chromosomes in the GnomAD database, including 35,128 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (5792 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29336 hom.)
• Consequence: NRG2 NM_004883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 9 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	NM_004883.3	MANE Select	c.991+13A>G		intron	N/A	NP_004874.1
	NRG2	NM_013982.3		c.991+13A>G		intron	N/A	NP_053585.1
	NRG2	NM_013983.3		c.991+13A>G		intron	N/A	NP_053586.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	ENST00000361474.6	TSL:1 MANE Select	c.991+13A>G		intron	N/A	ENSP00000354910.1
	NRG2	ENST00000358522.7	TSL:1	c.991+13A>G		intron	N/A	ENSP00000351323.3
	NRG2	ENST00000289422.11	TSL:5	c.991+13A>G		intron	N/A	ENSP00000289422.7

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37613 AN: 152056 Hom.: 5754 Cov.: 32

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.195 AC: 48566 AN: 249432 AF XY: 0.197

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.191 AC: 278928 AN: 1457292 Hom.: 29336 Cov.: 30 AF XY: 0.193 AC XY: 140277 AN XY: 725250

African (AFR) AF: 0.441 AC: 14739 AN: 33392

American (AMR) AF: 0.133 AC: 5932 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6756 AN: 26056

East Asian (EAS) AF: 0.126 AC: 4995 AN: 39686

South Asian (SAS) AF: 0.272 AC: 23461 AN: 86104

European-Finnish (FIN) AF: 0.111 AC: 5939 AN: 53402

Middle Eastern (MID) AF: 0.302 AC: 1731 AN: 5738

European-Non Finnish (NFE) AF: 0.183 AC: 202843 AN: 1108062

Other (OTH) AF: 0.208 AC: 12532 AN: 60222

GnomAD4 genome AF: 0.248 AC: 37710 AN: 152174 Hom.: 5792 Cov.: 32 AF XY: 0.243 AC XY: 18049 AN XY: 74398

African (AFR) AF: 0.431 AC: 17869 AN: 41506

American (AMR) AF: 0.170 AC: 2605 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 873 AN: 3472

East Asian (EAS) AF: 0.111 AC: 576 AN: 5166

South Asian (SAS) AF: 0.287 AC: 1384 AN: 4820

European-Finnish (FIN) AF: 0.104 AC: 1101 AN: 10604

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12463 AN: 67994

Other (OTH) AF: 0.243 AC: 514 AN: 2114

Alfa AF: 0.226 Hom.: 848

Bravo AF: 0.258

Asia WGS AF: 0.255 AC: 886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.31
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs889022; hg19: chr5-139260428; COSMIC: COSV56834221;