rs4252596

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000578199.5(ERBB2):c.-18+4400C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,516,162 control chromosomes in the GnomAD database, including 12,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.087 ( 821 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11519 hom. )

Consequence

ERBB2
ENST00000578199.5 intron

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.0150

Publications

25 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001347214).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
ERBB2	NM_001289936.2 link	c.22C>A	p.Pro8Thr	missense_variant	Exon 5 of 31	NP_001276865.1
ERBB2	XM_047435590.1 link	c.22C>A	p.Pro8Thr	missense_variant	Exon 6 of 32	XP_047291546.1
ERBB2	NM_001005862.3 link	c.-18+4400C>A		intron_variant	Intron 4 of 29	NP_001005862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein
ERBB2	ENST00000578199.5 link	c.-18+4400C>A		intron_variant	Intron 4 of 17	1	ENSP00000462808.1
ERBB2	ENST00000541774.5 link	c.22C>A	p.Pro8Thr	missense_variant	Exon 1 of 27	5	ENSP00000446466.1
ERBB2	ENST00000584601.5 link	c.-24C>A		5_prime_UTR_variant	Exon 5 of 31	2	ENSP00000462438.1
ERBB2	ENST00000406381.6 link	c.-18+4400C>A		intron_variant	Intron 1 of 26	5	ENSP00000385185.2

Frequencies

GnomAD3 genomes

AF:

0.0873

AC:

13284

AN:

152102

Hom.:

821

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0632

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.0680

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.0766

GnomAD2 exomes

AF:

0.108

AC:

13903

AN:

128144

AF XY:

0.120

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.0427

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.000767

Gnomad FIN exome

AF:

0.0663

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.123

AC:

167613

AN:

1363942

Hom.:

11519

Cov.:

AF XY:

0.126

AC XY:

85144

AN XY:

674070

show subpopulations

African (AFR)

AF:

0.0181

AC:

566

AN:

31302

American (AMR)

AF:

0.0473

AC:

1686

AN:

35636

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

4252

AN:

25020

East Asian (EAS)

AF:

0.000616

AC:

AN:

35688

South Asian (SAS)

AF:

0.195

AC:

15369

AN:

78624

European-Finnish (FIN)

AF:

0.0731

AC:

2444

AN:

33438

Middle Eastern (MID)

AF:

0.117

AC:

662

AN:

5656

European-Non Finnish (NFE)

AF:

0.128

AC:

135788

AN:

1061360

Other (OTH)

AF:

0.119

AC:

6824

AN:

57218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

6112

12224

18336

24448

30560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4856

9712

14568

19424

24280

<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:

0.0872

AC:

13280

AN:

152220

Hom.:

821

Cov.:

AF XY:

0.0835

AC XY:

6215

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0213

AC:

885

AN:

41534

American (AMR)

AF:

0.0631

AC:

965

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

590

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5186

South Asian (SAS)

AF:

0.179

AC:

861

AN:

4818

European-Finnish (FIN)

AF:

0.0680

AC:

721

AN:

10602

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9023

AN:

67996

Other (OTH)

AF:

0.0758

AC:

160

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

613

1227

1840

2454

3067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.115

Hom.:

1888

Bravo

AF:

0.0801

TwinsUK

AF:

0.121

AC:

448

ALSPAC

AF:

0.127

AC:

489

ExAC

AF:

0.143

AC:

2006

Asia WGS

AF:

0.0630

AC:

224

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

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

0.091

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.2

(source)

DANN

Benign

0.87

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

PhyloP100

-0.015

PROVEAN

Benign

0.61

REVEL

Benign

0.071

Sift

Benign

0.81

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.039

ClinPred

0.0063

GERP RS

-2.2

PromoterAI

-0.0066

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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