8-32649630-C-T

Variant names:

• chr8-32649630-C-T
• rs2466058
• NM_013964.5:c.502+32745C>T

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+32745C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,132 control chromosomes in the GnomAD database, including 1,187 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 0.11 (1187 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+32745C>T		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+32745C>T		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17312 AN: 152014 Hom.: 1186 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.0941

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0748

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.114 AC: 17332 AN: 152132 Hom.: 1187 Cov.: 32 AF XY: 0.114 AC XY: 8497 AN XY: 74364

African (AFR) AF: 0.187 AC: 7768 AN: 41488

American (AMR) AF: 0.112 AC: 1715 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0914 AC: 317 AN: 3468

East Asian (EAS) AF: 0.0943 AC: 488 AN: 5174

South Asian (SAS) AF: 0.124 AC: 596 AN: 4822

European-Finnish (FIN) AF: 0.0870 AC: 920 AN: 10572

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0748 AC: 5087 AN: 68002

Other (OTH) AF: 0.103 AC: 217 AN: 2110

Alfa AF: 0.0892 Hom.: 1941

Bravo AF: 0.119

Asia WGS AF: 0.109 AC: 380 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.029
DANN	Benign	0.57
PhyloP100		-2.7
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: rs2466058; hg19: chr8-32507149;