17-39720582-A-G

Position:

• chr17-39720582-A-G

Variant summary

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

The NM_004448.4(ERBB2):​c.1946+748A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,030 control chromosomes in the GnomAD database, including 32,006 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 (32006 hom., cov: 32)
• Consequence: ERBB2 NM_004448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.1946+748A>G		intron_variant		ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.1946+748A>G		intron_variant		1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97921 AN: 151912 Hom.: 31965 Cov.: 32

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.632

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

GnomAD4 genome AF: 0.645 AC: 98025 AN: 152030 Hom.: 32006 Cov.: 32 AF XY: 0.643 AC XY: 47814 AN XY: 74310

Gnomad4 AFR AF: 0.596

Gnomad4 AMR AF: 0.592

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.732

Gnomad4 FIN AF: 0.708

Gnomad4 NFE AF: 0.684

Gnomad4 OTH AF: 0.633

Alfa AF: 0.669 Hom.: 13129

Bravo AF: 0.629

Asia WGS AF: 0.633 AC: 2204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.62
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2952156; hg19: chr17-37876835;