NRG1 p.Gly46Arg

Variant names:

• chr8-32647853-G-C
• ENST00000520502.7:c.136G>C
• NRG1 p.Gly46Arg

Your query was ambiguous. Multiple possible variants found:

• chr8-32647853-G-C
• chr8-32647853-G-A
• chr8-32647853-GGG-CGT
• chr8-32647853-GGG-CGC
• chr8-32647853-GGG-CGA
• chr8-32647853-GGG-AGA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013959.4(NRG1):​c.136G>C​(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NRG1 NM_013959.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063976854).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013959.4. 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.502+30968G>C		intron	N/A	NP_039258.1	Q02297-1
	NRG1	NM_001322205.2		c.136G>C	p.Gly46Arg	missense	Exon 1 of 9	NP_001309134.1	A0A494C0Q4
	NRG1	NM_001322206.2		c.136G>C	p.Gly46Arg	missense	Exon 1 of 10	NP_001309135.1	A0A494C0L9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG1	ENST00000520502.7	TSL:1	c.136G>C	p.Gly46Arg	missense	Exon 1 of 3	ENSP00000433289.1	Q02297-10
	NRG1	ENST00000405005.8	TSL:1 MANE Select	c.502+30968G>C		intron	N/A	ENSP00000384620.2	Q02297-1
	NRG1	ENST00000287842.7	TSL:1	c.502+30968G>C		intron	N/A	ENSP00000287842.4	Q02297-6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.074
Sift	Benign	0.41	T
Sift4G	Benign	0.25	T
Mutation Taster		=97/3	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-32505372;