chr8-32657397-G-A

Variant names:

• chr8-32657397-G-A
• rs2466049
• NM_013964.5:c.502+40512G>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.502+40512G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 151,656 control chromosomes in the GnomAD database, including 904 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 0.10 (904 hom., cov: 31)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013964.5. 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
	NRG1	NM_013964.5	MANE Select	c.502+40512G>A		intron	N/A	NP_039258.1
	NRG1	NM_001322205.2		c.667+9013G>A		intron	N/A	NP_001309134.1
	NRG1	NM_013956.5		c.502+40512G>A		intron	N/A	NP_039250.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.502+40512G>A		intron	N/A	ENSP00000384620.2
	NRG1	ENST00000287842.7	TSL:1	c.502+40512G>A		intron	N/A	ENSP00000287842.4
	NRG1	ENST00000356819.7	TSL:1	c.502+40512G>A		intron	N/A	ENSP00000349275.6

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15453 AN: 151538 Hom.: 898 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0731

Gnomad OTH AF: 0.0868

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

GnomAD4 genome AF: 0.102 AC: 15479 AN: 151656 Hom.: 904 Cov.: 31 AF XY: 0.103 AC XY: 7594 AN XY: 74076

African (AFR) AF: 0.153 AC: 6315 AN: 41280

American (AMR) AF: 0.105 AC: 1607 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 331 AN: 3464

East Asian (EAS) AF: 0.106 AC: 540 AN: 5118

South Asian (SAS) AF: 0.0866 AC: 415 AN: 4794

European-Finnish (FIN) AF: 0.0860 AC: 904 AN: 10512

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0731 AC: 4968 AN: 67924

Other (OTH) AF: 0.0859 AC: 181 AN: 2108

Alfa AF: 0.0837 Hom.: 707

Bravo AF: 0.107

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		0.024
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: rs2466049; hg19: chr8-32514916;