Genetic Variant ERBB2:n.1081C>T (chr17-39712095-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000584908.5(ERBB2):n.1081C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,612,690 control chromosomes in the GnomAD database, including 364 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 0.026 ( 195 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 169 hom. )

Consequence

ERBB2
ENST00000584908.5 non_coding_transcript_exon

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -0.301

Publications

3 publications found

Variant links:

COSMIC-nc: COSV104371891

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 (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_004448.4 link	c.1021+48C>T		intron_variant	Intron 8 of 26	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.1021+48C>T		intron_variant	Intron 8 of 26	1	NM_004448.4	ENSP00000269571.4		P04626-1

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3989

AN:

152154

Hom.:

194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0923

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0168

GnomAD2 exomes

AF:

0.00703

AC:

1752

AN:

249316

AF XY:

0.00498

show subpopulations

Gnomad AFR exome

AF:

0.0981

Gnomad AMR exome

AF:

0.00370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000801

Gnomad OTH exome

AF:

0.00214

GnomAD4 exome

AF:

0.00263

AC:

3840

AN:

1460418

Hom.:

169

Cov.:

AF XY:

0.00220

AC XY:

1600

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.0951

AC:

3182

AN:

33460

American (AMR)

AF:

0.00398

AC:

178

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000627

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52604

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000900

AC:

100

AN:

1111630

Other (OTH)

AF:

0.00527

AC:

318

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

185

370

556

741

926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.0263

AC:

4000

AN:

152272

Hom.:

195

Cov.:

AF XY:

0.0249

AC XY:

1857

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0923

AC:

3832

AN:

41538

American (AMR)

AF:

0.00778

AC:

119

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68024

Other (OTH)

AF:

0.0166

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

168

336

505

673

841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0309

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.00260

AC:

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.6

(source)

DANN

Benign

0.62

PhyloP100

-0.30

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

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

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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