8-31640283-AGGCGGCGGC-AGGCGGCGGCGGC

Variant names:

• chr8-31640283-A-AGGC
• rs770519581
• ENST00000520407.5:c.314_316dupCGG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_013962.3(NRG1):​c.314_316dupCGG​(p.Ala105dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,120,206 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: NRG1 NM_013962.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRG1	NM_013962.3	c.314_316dupCGG	p.Ala105dup	disruptive_inframe_insertion	Exon 1 of 5		NP_039256.2
NRG1	XM_011544512.3	c.314_316dupCGG	p.Ala105dup	disruptive_inframe_insertion	Exon 1 of 13		XP_011542814.2
NRG1	XM_017013367.2	c.314_316dupCGG	p.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.314_316dupCGG	p.Ala105dup	disruptive_inframe_insertion	Exon 1 of 5	1		ENSP00000434640.1
NRG1	ENST00000650866.1	c.37+867_37+869dupCGG		intron_variant	Intron 1 of 12			ENSP00000499045.1
NRG1	ENST00000652698.1	c.37+867_37+869dupCGG		intron_variant	Intron 1 of 11			ENSP00000499008.1

Frequencies

GnomAD3 genomes AF: 0.000998 AC: 147 AN: 147338 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000404

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00378

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000907

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000287 AC: 279 AN: 972766 Hom.: 0 Cov.: 34 AF XY: 0.000297 AC XY: 136 AN XY: 458300

Gnomad4 AFR exome AF: 0.00270

Gnomad4 AMR exome AF: 0.000200

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00862

Gnomad4 SAS exome AF: 0.000108

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000834

Gnomad4 OTH exome AF: 0.000309

GnomAD4 genome AF: 0.000997 AC: 147 AN: 147440 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 77 AN XY: 71828

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.000404

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00380

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000907

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs770519581; hg19: chr8-31497799;