rs2934971

Positions:

• chr17-39698254-G-T

Variant summary

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

The ENST00000578199.5(ERBB2):​c.-18+3073G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 151,310 control chromosomes in the GnomAD database, including 33,272 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 0.66 (33272 hom., cov: 28)
• Consequence: ERBB2 ENST00000578199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_001005862.3	c.-18+3073G>T		intron_variant			NP_001005862.1
ERBB2	NM_001289936.2	c.-23-1283G>T		intron_variant			NP_001276865.1
ERBB2	NM_001289938.2	c.-18+3073G>T		intron_variant			NP_001276867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+3073G>T		intron_variant		1		ENSP00000462808
ERBB2	ENST00000406381.6	c.-18+3073G>T		intron_variant		5		ENSP00000385185
ERBB2	ENST00000584601.5	c.-68-1283G>T		intron_variant		2		ENSP00000462438

Frequencies

GnomAD3 genomes AF: 0.660 AC: 99753 AN: 151192 Hom.: 33225 Cov.: 28

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.653

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

GnomAD4 genome AF: 0.660 AC: 99864 AN: 151310 Hom.: 33272 Cov.: 28 AF XY: 0.658 AC XY: 48655 AN XY: 73888

Gnomad4 AFR AF: 0.642

Gnomad4 AMR AF: 0.600

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.400

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.654

Alfa AF: 0.667 Hom.: 9604

Bravo AF: 0.646

Asia WGS AF: 0.630 AC: 2169 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.12
DANN	Benign	0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2934971; hg19: chr17-37854507; COSMIC: COSV54079079; COSMIC: COSV54079079;