rs2934971

Variant names:

• chr17-39698254-G-T
• rs2934971
• ENST00000578199.5:c.-18+3073G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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]

ERBB2 Gene-Disease associations (from GenCC):

• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lung cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glioma susceptibility 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• visceral neuropathy, familial, 2, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-23-1283G>T		intron_variant	Intron 4 of 30		NP_001276865.1
ERBB2	NM_001005862.3	c.-18+3073G>T		intron_variant	Intron 4 of 29		NP_001005862.1
ERBB2	NM_001382782.1	c.-18+3073G>T		intron_variant	Intron 4 of 29		NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+3073G>T		intron_variant	Intron 4 of 17	1		ENSP00000462808.1
ERBB2	ENST00000406381.6	c.-18+3073G>T		intron_variant	Intron 1 of 26	5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-68-1283G>T		intron_variant	Intron 4 of 30	2		ENSP00000462438.1

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

African (AFR) AF: 0.642 AC: 26457 AN: 41200

American (AMR) AF: 0.600 AC: 9105 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2452 AN: 3466

East Asian (EAS) AF: 0.400 AC: 2039 AN: 5096

South Asian (SAS) AF: 0.734 AC: 3513 AN: 4784

European-Finnish (FIN) AF: 0.710 AC: 7421 AN: 10446

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46573 AN: 67824

Other (OTH) AF: 0.654 AC: 1379 AN: 2108

Alfa AF: 0.664 Hom.: 10693

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
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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