rs144019910

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004448.4(ERBB2):c.140G>A(p.Arg47His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,607,510 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 5 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 3.48

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the ERBB2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 3.2497 (above the threshold of 3.09). Trascript score misZ: 4.234 (above the threshold of 3.09). GenCC associations: The gene is linked to visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.008545518).

BP6

Variant 17-39707056-G-A is Benign according to our data. Variant chr17-39707056-G-A is described in ClinVar as [Benign]. Clinvar id is 134075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152224) while in subpopulation AMR AF= 0.000784 (12/15298). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 27	ENST00000269571.10	NP_004439.2	P04626-1X5DNK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10 link	c.140G>A	p.Arg47His	missense_variant	Exon 2 of 27	1	NM_004448.4	ENSP00000269571.4		P04626-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000714

AC:

174

AN:

243822

Hom.:

AF XY:

0.000734

AC XY:

AN XY:

132210

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000455

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000677

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000261

Gnomad OTH exome

AF:

0.00120

GnomAD4 exome

AF:

0.000456

AC:

664

AN:

1455286

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

348

AN XY:

723906

show subpopulations

Gnomad4 AFR exome

AF:

0.000302

Gnomad4 AMR exome

AF:

0.000614

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000822

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.000578

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.000930

Hom.:

Bravo

AF:

0.000699

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000535

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.58

.;.;.;.;.;D;T

Eigen

Benign

-0.020

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

.;D;D;D;D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.3

.;.;.;.;.;L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

.;.;N;N;.;N;.

REVEL

Benign

0.28

Sift

Benign

0.080

.;.;T;T;.;T;.

Sift4G

Benign

0.11

T;T;T;T;T;T;D

Polyphen

0.12, 0.054, 0.011

.;B;.;B;.;B;.

Vest4

0.29

MVP

0.78

MPC

0.43

ClinPred

0.029

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.23

gMVP

0.63

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