rs2439305

Variant names:

• chr8-32571946-G-A
• rs2439305
• NM_013964.5:c.100+23120G>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.100+23120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,900 control chromosomes in the GnomAD database, including 22,738 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 0.54 (22738 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.662
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.100+23120G>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.100+23120G>A		intron_variant	Intron 1 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82538 AN: 151782 Hom.: 22729 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.565

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

GnomAD4 genome AF: 0.544 AC: 82584 AN: 151900 Hom.: 22738 Cov.: 32 AF XY: 0.541 AC XY: 40144 AN XY: 74202

African (AFR) AF: 0.541 AC: 22392 AN: 41414

American (AMR) AF: 0.483 AC: 7379 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2133 AN: 3468

East Asian (EAS) AF: 0.828 AC: 4270 AN: 5158

South Asian (SAS) AF: 0.592 AC: 2856 AN: 4826

European-Finnish (FIN) AF: 0.446 AC: 4692 AN: 10526

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36988 AN: 67934

Other (OTH) AF: 0.564 AC: 1191 AN: 2110

Alfa AF: 0.533 Hom.: 3620

Bravo AF: 0.546

Asia WGS AF: 0.639 AC: 2219 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.9
DANN	Benign	0.42
PhyloP100		-0.66
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: rs2439305; hg19: chr8-32429464;