8-32658536-T-G

Variant names:

• chr8-32658536-T-G
• rs2466048
• NM_013964.5:c.502+41651T>G

Variant summary

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

The NM_013964.5(NRG1):​c.502+41651T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 151,898 control chromosomes in the GnomAD database, including 21,070 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 0.52 (21070 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+41651T>G		intron_variant	Intron 5 of 11	ENST00000405005.8	NP_039258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000405005.8	c.502+41651T>G		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78627 AN: 151780 Hom.: 21048 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.493

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

GnomAD4 genome AF: 0.518 AC: 78700 AN: 151898 Hom.: 21070 Cov.: 32 AF XY: 0.523 AC XY: 38806 AN XY: 74236

African (AFR) AF: 0.578 AC: 23924 AN: 41416

American (AMR) AF: 0.602 AC: 9183 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1506 AN: 3468

East Asian (EAS) AF: 0.845 AC: 4364 AN: 5166

South Asian (SAS) AF: 0.501 AC: 2418 AN: 4824

European-Finnish (FIN) AF: 0.526 AC: 5542 AN: 10540

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30090 AN: 67912

Other (OTH) AF: 0.491 AC: 1035 AN: 2106

Alfa AF: 0.472 Hom.: 52198

Bravo AF: 0.530

Asia WGS AF: 0.618 AC: 2147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.33
DANN	Benign	0.44
PhyloP100		-0.58
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: rs2466048; hg19: chr8-32516055;