rs2954041

Variant names:

• chr8-32665107-G-T
• rs2954041
• NM_013964.5:c.502+48222G>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+48222G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 152,188 control chromosomes in the GnomAD database, including 642 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 0.052 (642 hom., cov: 32)
• Consequence: NRG1 NM_013964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• Publications: 11 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 (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013964.5	c.502+48222G>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+48222G>T		intron_variant	Intron 5 of 11	1	NM_013964.5	ENSP00000384620.2

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7931 AN: 152070 Hom.: 644 Cov.: 32

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.0868

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0492

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

GnomAD4 genome AF: 0.0521 AC: 7934 AN: 152188 Hom.: 642 Cov.: 32 AF XY: 0.0555 AC XY: 4131 AN XY: 74406

African (AFR) AF: 0.0518 AC: 2151 AN: 41522

American (AMR) AF: 0.136 AC: 2084 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.374 AC: 1931 AN: 5170

South Asian (SAS) AF: 0.0864 AC: 417 AN: 4824

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 965 AN: 67998

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0520 Hom.: 104

Bravo AF: 0.0639

Asia WGS AF: 0.187 AC: 651 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.59
PhyloP100		-0.57
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: rs2954041; hg19: chr8-32522626;