NM_004448.4:c.1960A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004448.4(ERBB2):c.1960A>G(p.Ile654Val) variant causes a missense change. The variant allele was found at a frequency of 0.00808 in 1,607,662 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0084 ( 61 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 4.53

Publications

47 publications found

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 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)

ERBB2 links:

ENSG00000305964 (HGNC:):

ENSG00000305964 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003094107).

BP6

Variant 17-39723332-A-G is Benign according to our data. Variant chr17-39723332-A-G is described in ClinVar as Benign. ClinVar VariationId is 13874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00515 (772/150010) while in subpopulation NFE AF = 0.00835 (564/67522). AF 95% confidence interval is 0.00778. There are 3 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 772 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.1960A>G	p.Ile654Val	missense_variant	Exon 17 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.1960A>G	p.Ile654Val	missense_variant	Exon 17 of 27	1	NM_004448.4	ENSP00000269571.4		P04626-1

Frequencies

GnomAD3 genomes

AF:

0.00515

AC:

772

AN:

149896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00430

Gnomad ASJ

AF:

0.00232

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00171

Gnomad FIN

AF:

0.000883

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00835

Gnomad OTH

AF:

0.00771

GnomAD2 exomes

AF:

0.00490

AC:

1231

AN:

251420

AF XY:

0.00480

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00824

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00838

AC:

12215

AN:

1457652

Hom.:

Cov.:

AF XY:

0.00810

AC XY:

5876

AN XY:

725238

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

33364

American (AMR)

AF:

0.00363

AC:

162

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00209

AC:

180

AN:

86216

European-Finnish (FIN)

AF:

0.00177

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.00331

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0102

AC:

11273

AN:

1109604

Other (OTH)

AF:

0.00645

AC:

388

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

577

1153

1730

2306

2883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00515

AC:

772

AN:

150010

Hom.:

Cov.:

AF XY:

0.00484

AC XY:

354

AN XY:

73188

show subpopulations

African (AFR)

AF:

0.00221

AC:

AN:

40654

American (AMR)

AF:

0.00430

AC:

AN:

15130

Ashkenazi Jewish (ASJ)

AF:

0.00232

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00171

AC:

AN:

4678

European-Finnish (FIN)

AF:

0.000883

AC:

AN:

10196

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00835

AC:

564

AN:

67522

Other (OTH)

AF:

0.00763

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00656

Hom.:

Bravo

AF:

0.00549

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.00480

AC:

583

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.00818

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERBB2: PP2, BP4, BS1, BS2 -

Jan 12, 2025

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

- -

ERBB2 POLYMORPHISM

Benign:1

Feb 01, 1993

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

0.086

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.24

.;.;.;T;.;T

Eigen

Benign

-0.0084

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.85

.;T;D;D;T;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.0031

T;T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.9

.;.;.;.;.;L

PhyloP100

4.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.17

.;N;N;N;.;N

REVEL

Uncertain

0.33

Sift

Benign

0.16

.;T;T;T;.;T

Sift4G

Benign

0.36

T;T;T;T;T;T

Polyphen

0.12, 0.20, 0.30

.;.;B;B;.;B

Vest4

0.15

MVP

0.84

MPC

1.1

ClinPred

0.011

GERP RS

5.0

Varity_R

0.15

gMVP

0.70

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over