rs141116145

Positions:

Variant summary

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

The NM_004448.4(ERBB2):c.1157C>A(p.Ala386Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,613,984 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 22 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.260

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=0.005045682).

BP6

Variant 17-39715294-C-A is Benign according to our data. Variant chr17-39715294-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 134068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-39715294-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00334 (509/152284) while in subpopulation AMR AF= 0.00621 (95/15304). AF 95% confidence interval is 0.0052. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4 linkuse as main transcript	c.1157C>A	p.Ala386Asp	missense_variant	10/27	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.1157C>A	p.Ala386Asp	missense_variant	10/27	1	NM_004448.4	ENSP00000269571	P1	P04626-1

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00488

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00379

AC:

951

AN:

250936

Hom.:

AF XY:

0.00387

AC XY:

525

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00404

AC:

5904

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

2877

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00512

Gnomad4 ASJ exome

AF:

0.00444

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00109

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.00459

Gnomad4 OTH exome

AF:

0.00341

GnomAD4 genome

AF:

0.00334

AC:

509

AN:

152284

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00488

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00501

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00345

AC:

419

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.091

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.38

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

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.66

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

M_CAP

Benign

0.014

MetaRNN

Benign

0.0050

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.47

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

REVEL

Benign

0.036

Sift

Benign

0.16

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

Sift4G

Benign

0.16

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

Polyphen

0.0

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

Vest4

0.25

MVP

0.39

MPC

0.52

ClinPred

0.0084

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.32

gMVP

0.71

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

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