17-39715782-G-T

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.1356G>T(p.Trp452Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,608,802 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 39 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

Publications

24 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:

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=0.007810861).

BP6

Variant 17-39715782-G-T is Benign according to our data. Variant chr17-39715782-G-T is described in ClinVar as Benign. ClinVar VariationId is 134072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2118/152324) while in subpopulation AFR AF = 0.0484 (2011/41572). AF 95% confidence interval is 0.0466. There are 56 homozygotes in GnomAd4. There are 1022 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2118 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.1356G>T	p.Trp452Cys	missense_variant	Exon 12 of 27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10 link	c.1356G>T	p.Trp452Cys	missense_variant	Exon 12 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes

AF:

0.0139

AC:

2109

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00373

AC:

921

AN:

247046

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00129

AC:

1872

AN:

1456478

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

817

AN XY:

724840

show subpopulations

African (AFR)

AF:

0.0449

AC:

1502

AN:

33480

American (AMR)

AF:

0.00239

AC:

107

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48080

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111982

Other (OTH)

AF:

0.00336

AC:

203

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.0139

AC:

2118

AN:

152324

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1022

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0484

AC:

2011

AN:

41572

American (AMR)

AF:

0.00464

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68022

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

202

303

404

505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00338

Hom.:

Bravo

AF:

0.0157

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00445

AC:

540

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 29, 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

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERBB2: BP4, BS1, BS2

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

Uncertain

0.49

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0

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

Eigen

Benign

-0.054

Eigen_PC

Benign

-0.072

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.0

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

MetaRNN

Benign

0.0078

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

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.0

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

PhyloP100

1.3

PrimateAI

Benign

0.44

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.029

D;D;D;D;D;D;D

Vest4

0.41

ClinPred

0.049

GERP RS

2.8

Varity_R

0.38

gMVP

0.79

Mutation Taster

=98/2

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