chr8-32574851-G-C

Variant names:

• chr8-32574851-G-C
• rs2439302
• NM_013964.5:c.101-20977G>C

Variant summary

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

The NM_013964.5(NRG1):​c.101-20977G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 152,062 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: -0.347
• Publications: 79 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	NM_013964.5	MANE Select	c.101-20977G>C		intron	N/A	NP_039258.1	Q02297-1
	NRG1	NM_013956.5		c.101-20977G>C		intron	N/A	NP_039250.2	Q02297-6
	NRG1	NM_013957.5		c.101-20977G>C		intron	N/A	NP_039251.2	Q02297-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.101-20977G>C		intron	N/A	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.101-20977G>C		intron	N/A	ENSP00000287842.4	Q02297-6
	NRG1	ENST00000356819.7	TSL:1	c.101-20977G>C		intron	N/A	ENSP00000349275.6	Q02297-7

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82588 AN: 151944 Hom.: 22729 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.543 AC: 82634 AN: 152062 Hom.: 22738 Cov.: 32 AF XY: 0.541 AC XY: 40202 AN XY: 74334

African (AFR) AF: 0.540 AC: 22407 AN: 41466

American (AMR) AF: 0.484 AC: 7392 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2135 AN: 3470

East Asian (EAS) AF: 0.827 AC: 4271 AN: 5162

South Asian (SAS) AF: 0.592 AC: 2853 AN: 4818

European-Finnish (FIN) AF: 0.446 AC: 4702 AN: 10554

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.544 AC: 36993 AN: 67996

Other (OTH) AF: 0.566 AC: 1195 AN: 2112

Alfa AF: 0.559 Hom.: 13314

Bravo AF: 0.546

Asia WGS AF: 0.640 AC: 2226 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.43
DANN	Benign	0.81
PhyloP100		-0.35
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: rs2439302; hg19: chr8-32432369; COSMIC: COSV55153890;