rs2643195

Positions:

• chr17-39696865-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001289936.2(ERBB2):​c.-24+1684A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,044 control chromosomes in the GnomAD database, including 27,492 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 0.58 (27458 hom., cov: 30)
  • Exomes 𝑓: 0.57 (34 hom.)
• Consequence: ERBB2 NM_001289936.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.858

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-24+1684A>G		intron_variant			NP_001276865.1
ERBB2	NM_001005862.3	c.-18+1684A>G		intron_variant			NP_001005862.1
ERBB2	NM_001382782.1	c.-18+1684A>G		intron_variant			NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+1684A>G		intron_variant		1		ENSP00000462808.1
ERBB2	ENST00000406381.6	c.-18+1684A>G		intron_variant		5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-69+1684A>G		intron_variant		2		ENSP00000462438.1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88485 AN: 151730 Hom.: 27435 Cov.: 30

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.571 AC: 112 AN: 196 Hom.: 34 AF XY: 0.636 AC XY: 84 AN XY: 132

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.612

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.583 AC: 88548 AN: 151848 Hom.: 27458 Cov.: 30 AF XY: 0.583 AC XY: 43275 AN XY: 74172

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.573

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.733

Gnomad4 FIN AF: 0.708

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.594

Alfa AF: 0.667 Hom.: 43196

Bravo AF: 0.558

Asia WGS AF: 0.623 AC: 2168 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.82
DANN	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2643195; hg19: chr17-37853118;