chr17-39723335-A-G

Position:

chr17-39723335-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000269571.10(ERBB2):c.1963A>G(p.Ile655Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,611,762 control chromosomes in the GnomAD database, including 42,083 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2846 hom., cov: 31)

Exomes 𝑓: 0.23 ( 39237 hom. )

Consequence

ERBB2
ENST00000269571.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 3.57

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB2. . Gene score misZ 3.2497 (greater than the threshold 3.09). Trascript score misZ 4.234 (greater than threshold 3.09). GenCC has associacion of gene with visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013844967).

BP6

Variant 17-39723335-A-G is Benign according to our data. Variant chr17-39723335-A-G is described in ClinVar as [Benign]. Clinvar id is 13873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4 linkuse as main transcript	c.1963A>G	p.Ile655Val	missense_variant	17/27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10 linkuse as main transcript	c.1963A>G	p.Ile655Val	missense_variant	17/27	1	NM_004448.4	ENSP00000269571	P1	P04626-1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26137

AN:

149944

Hom.:

2844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0440

Gnomad AMI

AF:

0.271

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.241

Gnomad OTH

AF:

0.163

GnomAD3 exomes

AF:

0.196

AC:

49359

AN:

251376

Hom.:

5514

AF XY:

0.198

AC XY:

26902

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.294

Gnomad NFE exome

AF:

0.239

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.226

AC:

329782

AN:

1461700

Hom.:

39237

Cov.:

AF XY:

0.223

AC XY:

162492

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0352

Gnomad4 AMR exome

AF:

0.158

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.126

Gnomad4 SAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.297

Gnomad4 NFE exome

AF:

0.243

Gnomad4 OTH exome

AF:

0.201

GnomAD4 genome

AF:

0.174

AC:

26140

AN:

150062

Hom.:

2846

Cov.:

AF XY:

0.176

AC XY:

12858

AN XY:

73220

show subpopulations

Gnomad4 AFR

AF:

0.0439

Gnomad4 AMR

AF:

0.167

Gnomad4 ASJ

AF:

0.139

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.303

Gnomad4 NFE

AF:

0.241

Gnomad4 OTH

AF:

0.161

Alfa

AF:

0.219

Hom.:

6899

Bravo

AF:

0.156

TwinsUK

AF:

0.222

AC:

823

ALSPAC

AF:

0.238

AC:

917

ESP6500AA

AF:

0.0481

AC:

212

ESP6500EA

AF:

0.230

AC:

1980

ExAC

AF:

0.196

AC:

23831

Asia WGS

AF:

0.152

AC:

528

AN:

3478

EpiCase

AF:

0.222

EpiControl

AF:

0.214

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

ERBB2 POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Feb 01, 1993

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.23

.;.;.;T;.;T

Eigen

Benign

-0.020

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

.;T;T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;.;.;.;L

MutationTaster

Benign

0.030

P;P;P;P;P;P;P

PrimateAI

Benign

0.45

PROVEAN

Benign

0.46

.;N;N;N;.;N

REVEL

Benign

0.21

Sift

Benign

1.0

.;T;T;T;.;T

Sift4G

Benign

0.81

T;T;T;T;T;T

Polyphen

0.68, 0.41

.;.;P;B;.;B

Vest4

0.068

MPC

1.1

ClinPred

0.017

GERP RS

5.0

Varity_R

0.18

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over