rs2466067

Variant names:

• chr8-32580476-G-A
• rs2466067
• NM_013964.5:c.101-15352G>A

Variant summary

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

The NM_013964.5(NRG1):​c.101-15352G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,152 control chromosomes in the GnomAD database, including 26,084 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 0.56 (26084 hom., cov: 33)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.971
• Publications: 8 publications found

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

• schizophrenia 6

  Inheritance: AR 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=-0.68).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.101-15352G>A		intron_variant	Intron 1 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.101-15352G>A		intron_variant	Intron 1 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84971 AN: 152034 Hom.: 26069 Cov.: 33

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.594

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

GnomAD4 genome AF: 0.559 AC: 85002 AN: 152152 Hom.: 26084 Cov.: 33 AF XY: 0.558 AC XY: 41527 AN XY: 74408

African (AFR) AF: 0.307 AC: 12751 AN: 41492

American (AMR) AF: 0.669 AC: 10226 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2317 AN: 3472

East Asian (EAS) AF: 0.247 AC: 1281 AN: 5176

South Asian (SAS) AF: 0.580 AC: 2792 AN: 4816

European-Finnish (FIN) AF: 0.647 AC: 6858 AN: 10596

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46689 AN: 68000

Other (OTH) AF: 0.600 AC: 1265 AN: 2110

Alfa AF: 0.665 Hom.: 48704

Bravo AF: 0.548

Asia WGS AF: 0.456 AC: 1581 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.9
DANN	Benign	0.85
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2466067; hg19: chr8-32437994; COSMIC: COSV55177490;