17-39705465-T-C

Variant names:

• chr17-39705465-T-C
• rs2952155
• NM_004448.4:c.74-1525T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004448.4(ERBB2):​c.74-1525T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 151,960 control chromosomes in the GnomAD database, including 37,243 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 0.70 (37243 hom., cov: 31)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• Publications: 29 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.74-1525T>C		intron_variant	Intron 1 of 26	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.74-1525T>C		intron_variant	Intron 1 of 26	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105539 AN: 151842 Hom.: 37213 Cov.: 31

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.755

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.694

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

GnomAD4 genome AF: 0.695 AC: 105626 AN: 151960 Hom.: 37243 Cov.: 31 AF XY: 0.693 AC XY: 51465 AN XY: 74258

African (AFR) AF: 0.631 AC: 26163 AN: 41442

American (AMR) AF: 0.652 AC: 9952 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 2621 AN: 3472

East Asian (EAS) AF: 0.399 AC: 2054 AN: 5142

South Asian (SAS) AF: 0.747 AC: 3593 AN: 4810

European-Finnish (FIN) AF: 0.755 AC: 7991 AN: 10580

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50824 AN: 67928

Other (OTH) AF: 0.694 AC: 1464 AN: 2108

Alfa AF: 0.724 Hom.: 12775

Bravo AF: 0.680

Asia WGS AF: 0.638 AC: 2222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.29
DANN	Benign	0.44
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2952155; hg19: chr17-37861718;