17-39709752-C-T

Position:

• chr17-39709752-C-T

Variant summary

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

The NM_004448.4(ERBB2):​c.575-61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,490,454 control chromosomes in the GnomAD database, including 346,925 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 0.64 (31234 hom., cov: 32)
  • Exomes 𝑓: 0.68 (315691 hom.)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.322

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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.575-61C>T		intron_variant		ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.575-61C>T		intron_variant		1	NM_004448.4	ENSP00000269571	P1

Frequencies

GnomAD3 genomes AF: 0.636 AC: 96582 AN: 151912 Hom.: 31202 Cov.: 32

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.710

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.627

GnomAD4 exome AF: 0.684 AC: 915271 AN: 1338424 Hom.: 315691 AF XY: 0.687 AC XY: 462220 AN XY: 672456

Gnomad4 AFR exome AF: 0.562

Gnomad4 AMR exome AF: 0.601

Gnomad4 ASJ exome AF: 0.721

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.706

Gnomad4 NFE exome AF: 0.692

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.636 AC: 96670 AN: 152030 Hom.: 31234 Cov.: 32 AF XY: 0.634 AC XY: 47125 AN XY: 74302

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.731

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.629

Alfa AF: 0.673 Hom.: 15779

Bravo AF: 0.619

Asia WGS AF: 0.630 AC: 2194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1810132; hg19: chr17-37866005; COSMIC: COSV54069292; COSMIC: COSV54069292;