chr17-39709752-C-T

Variant names:

• chr17-39709752-C-T
• rs1810132
• NM_004448.4:c.575-61C>T

Variant summary

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

The NM_001382784.1(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_001382784.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.322
• Publications: 48 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382784.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	NM_004448.4	MANE Select	c.575-61C>T		intron	N/A	NP_004439.2
	ERBB2	NM_001382784.1		c.575-61C>T		intron	N/A	NP_001369713.1
	ERBB2	NM_001382785.1		c.575-61C>T		intron	N/A	NP_001369714.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.575-61C>T		intron	N/A	ENSP00000269571.4
	ERBB2	ENST00000584450.5	TSL:1	c.575-61C>T		intron	N/A	ENSP00000463714.1
	ERBB2	ENST00000578199.5	TSL:1	c.485-61C>T		intron	N/A	ENSP00000462808.1

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

African (AFR) AF: 0.562 AC: 17436 AN: 31022

American (AMR) AF: 0.601 AC: 26626 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 18317 AN: 25422

East Asian (EAS) AF: 0.447 AC: 17418 AN: 39002

South Asian (SAS) AF: 0.764 AC: 63962 AN: 83678

European-Finnish (FIN) AF: 0.706 AC: 32271 AN: 45718

Middle Eastern (MID) AF: 0.767 AC: 4259 AN: 5550

European-Non Finnish (NFE) AF: 0.692 AC: 696822 AN: 1007168

Other (OTH) AF: 0.675 AC: 38160 AN: 56570

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

African (AFR) AF: 0.563 AC: 23351 AN: 41470

American (AMR) AF: 0.587 AC: 8966 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 2463 AN: 3470

East Asian (EAS) AF: 0.398 AC: 2057 AN: 5162

South Asian (SAS) AF: 0.731 AC: 3529 AN: 4826

European-Finnish (FIN) AF: 0.709 AC: 7493 AN: 10570

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46562 AN: 67936

Other (OTH) AF: 0.629 AC: 1328 AN: 2112

Alfa AF: 0.671 Hom.: 18469

Bravo AF: 0.619

Asia WGS AF: 0.630 AC: 2194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.31
PhyloP100		-0.32
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: rs1810132; hg19: chr17-37866005; COSMIC: COSV54069292; COSMIC: COSV54069292;