rs10515508

Variant names:

• chr5-139995485-T-C
• rs10515508
• NM_004883.3:c.700+46885A>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.700+46885A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,116 control chromosomes in the GnomAD database, including 2,335 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 0.16 (2335 hom., cov: 32)
• Consequence: NRG2 NM_004883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 2 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG2	NM_004883.3	c.700+46885A>G		intron_variant	Intron 1 of 9	ENST00000361474.6	NP_004874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG2	ENST00000361474.6	c.700+46885A>G		intron_variant	Intron 1 of 9	1	NM_004883.3	ENSP00000354910.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23626 AN: 151998 Hom.: 2321 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.156 AC: 23661 AN: 152116 Hom.: 2335 Cov.: 32 AF XY: 0.153 AC XY: 11362 AN XY: 74358

African (AFR) AF: 0.0414 AC: 1718 AN: 41512

American (AMR) AF: 0.223 AC: 3410 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 508 AN: 3472

East Asian (EAS) AF: 0.102 AC: 528 AN: 5182

South Asian (SAS) AF: 0.0971 AC: 468 AN: 4820

European-Finnish (FIN) AF: 0.175 AC: 1844 AN: 10566

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.216 AC: 14674 AN: 67972

Other (OTH) AF: 0.178 AC: 375 AN: 2106

Alfa AF: 0.188 Hom.: 362

Bravo AF: 0.159

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.68
PhyloP100		-0.75
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: rs10515508; hg19: chr5-139375070; COSMIC: COSV56833078;