dbSNP rs61737968: ERBB2:p.Glu79Ala (chr17-39708331-A-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_004448.4(ERBB2):c.236A>C(p.Glu79Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,613,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.05

Publications

11 publications found

Variant links:

COSMIC-nc: COSV104371929

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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.012415707).

BP6

Variant 17-39708331-A-C is Benign according to our data. Variant chr17-39708331-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 134087.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 = 0.0028 (426/152276) while in subpopulation AFR AF = 0.00953 (396/41566). AF 95% confidence interval is 0.00875. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 426 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERBB2	NM_004448.4	MANE Select	c.236A>C	p.Glu79Ala	missense	Exon 3 of 27	NP_004439.2
ERBB2	NM_001382784.1		c.236A>C	p.Glu79Ala	missense	Exon 3 of 28	NP_001369713.1
ERBB2	NM_001382785.1		c.236A>C	p.Glu79Ala	missense	Exon 3 of 28	NP_001369714.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.236A>C	p.Glu79Ala	missense	Exon 3 of 27	ENSP00000269571.4
ERBB2	ENST00000584450.5	TSL:1	c.236A>C	p.Glu79Ala	missense	Exon 3 of 26	ENSP00000463714.1
ERBB2	ENST00000578199.5	TSL:1	c.146A>C	p.Glu49Ala	missense	Exon 6 of 18	ENSP00000462808.1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

425

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00953

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000833

AC:

209

AN:

251006

AF XY:

0.000715

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000329

AC:

481

AN:

1460782

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

215

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.0111

AC:

373

AN:

33462

American (AMR)

AF:

0.000850

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111110

Other (OTH)

AF:

0.000861

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00280

AC:

426

AN:

152276

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00953

AC:

396

AN:

41566

American (AMR)

AF:

0.00163

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

105

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:

0.000845

Hom.:

Bravo

AF:

0.00336

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000923

AC:

112

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

3.6

PhyloP100

9.1

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.73

MVP

0.95

MPC

1.1

ClinPred

0.12

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.88

Mutation Taster

=24/76

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over