8-31640283-AGGCGGCGGC-AGGCGGCGGCGGCGGCGGC

Variant names:

• chr8-31640283-A-AGGCGGCGGC
• rs770519581
• ENST00000520407.5:c.308_316dupCGGCGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000520407.5(NRG1):​c.308_316dupCGGCGGCGG​(p.Ala103_Ala105dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRG1 ENST00000520407.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• 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

ENSG00000302325 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013962.3	c.308_316dupCGGCGGCGG	p.Ala103_Ala105dup	disruptive_inframe_insertion	Exon 1 of 5		NP_039256.2
NRG1	XM_011544512.3	c.308_316dupCGGCGGCGG	p.Ala103_Ala105dup	disruptive_inframe_insertion	Exon 1 of 13		XP_011542814.2
NRG1	XM_017013367.2	c.308_316dupCGGCGGCGG	p.Ala103_Ala105dup	disruptive_inframe_insertion	Exon 1 of 11		XP_016868856.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.308_316dupCGGCGGCGG	p.Ala103_Ala105dup	disruptive_inframe_insertion	Exon 1 of 5	1		ENSP00000434640.1
NRG1	ENST00000650866.1	c.37+861_37+869dupCGGCGGCGG		intron_variant	Intron 1 of 12			ENSP00000499045.1
NRG1	ENST00000652698.1	c.37+861_37+869dupCGGCGGCGG		intron_variant	Intron 1 of 11			ENSP00000499008.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

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

Other links and lift over

dbSNP: rs770519581; hg19: chr8-31497799;