17-39727784-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004448.4(ERBB2):c.3508C>G(p.Pro1170Ala) variant causes a missense change. The variant allele was found at a frequency of 0.642 in 1,612,086 control chromosomes in the GnomAD database, including 341,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 23709 hom., cov: 32)

Exomes 𝑓: 0.65 ( 317939 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.29

Publications

184 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=1.0380236E-5).

BP6

Variant 17-39727784-C-G is Benign according to our data. Variant chr17-39727784-C-G is described in ClinVar as Benign. ClinVar VariationId is 134082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.3508C>G	p.Pro1170Ala	missense_variant	Exon 27 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.3508C>G	p.Pro1170Ala	missense_variant	Exon 27 of 27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79394

AN:

151918

Hom.:

23697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.771

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.676

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.682

Gnomad MID

AF:

0.620

Gnomad NFE

AF:

0.663

Gnomad OTH

AF:

0.540

GnomAD2 exomes

AF:

0.609

AC:

152231

AN:

249792

AF XY:

0.625

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.569

Gnomad ASJ exome

AF:

0.689

Gnomad EAS exome

AF:

0.366

Gnomad FIN exome

AF:

0.682

Gnomad NFE exome

AF:

0.673

Gnomad OTH exome

AF:

0.634

GnomAD4 exome

AF:

0.654

AC:

955482

AN:

1460050

Hom.:

317939

Cov.:

AF XY:

0.657

AC XY:

477227

AN XY:

726106

show subpopulations

African (AFR)

AF:

0.220

AC:

7376

AN:

33456

American (AMR)

AF:

0.565

AC:

25214

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.685

AC:

17821

AN:

26020

East Asian (EAS)

AF:

0.443

AC:

17569

AN:

39678

South Asian (SAS)

AF:

0.694

AC:

59769

AN:

86064

European-Finnish (FIN)

AF:

0.677

AC:

36119

AN:

53380

Middle Eastern (MID)

AF:

0.702

AC:

4038

AN:

5756

European-Non Finnish (NFE)

AF:

0.675

AC:

749705

AN:

1110778

Other (OTH)

AF:

0.628

AC:

37871

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

18720

37439

56159

74878

93598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19170

38340

57510

76680

95850

<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:

0.522

AC:

79420

AN:

152036

Hom.:

23709

Cov.:

AF XY:

0.522

AC XY:

38817

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.228

AC:

9459

AN:

41470

American (AMR)

AF:

0.532

AC:

8128

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.676

AC:

2346

AN:

3470

East Asian (EAS)

AF:

0.395

AC:

2027

AN:

5132

South Asian (SAS)

AF:

0.661

AC:

3182

AN:

4814

European-Finnish (FIN)

AF:

0.682

AC:

7220

AN:

10594

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.663

AC:

45034

AN:

67956

Other (OTH)

AF:

0.541

AC:

1142

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1685

3370

5055

6740

8425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.632

Hom.:

10206

Bravo

AF:

0.495

TwinsUK

AF:

0.670

AC:

2486

ALSPAC

AF:

0.667

AC:

2571

ESP6500AA

AF:

0.234

AC:

1033

ESP6500EA

AF:

0.657

AC:

5646

ExAC

AF:

0.605

AC:

73474

Asia WGS

AF:

0.559

AC:

1945

AN:

3478

EpiCase

AF:

0.679

EpiControl

AF:

0.672

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 04, 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

- -

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

0.096

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;.;.;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

.;T;T;T;T

MetaRNN

Benign

0.000010

T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

.;.;.;.;N

PhyloP100

4.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

.;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.030

.;D;D;D;D

Sift4G

Benign

0.15

T;T;T;T;T

Polyphen

0.74, 0.94, 0.95

.;.;P;P;P

Vest4

0.17

MPC

0.93

ClinPred

0.034

GERP RS

5.0

Varity_R

0.12

gMVP

0.15

Mutation Taster

=60/40

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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