Genetic Variant ERBB2:p.Leu15Phe (chr17-39700281-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004448.4(ERBB2):c.43C>T(p.Leu15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,432,762 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 3 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 3.02

Publications

6 publications found

Variant links:

COSMIC-nc: COSV54067770

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025525242).

BP6

Variant 17-39700281-C-T is Benign according to our data. Variant chr17-39700281-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 134067.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000545 (83/152246) while in subpopulation SAS AF = 0.000829 (4/4824). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 83 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	UniProt
ERBB2	NM_004448.4	MANE Select	c.43C>T	p.Leu15Phe	missense	Exon 1 of 27	NP_004439.2	P04626-1
ERBB2	NM_001382784.1		c.43C>T	p.Leu15Phe	missense	Exon 1 of 28	NP_001369713.1
ERBB2	NM_001382785.1		c.43C>T	p.Leu15Phe	missense	Exon 1 of 28	NP_001369714.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERBB2	ENST00000269571.10	TSL:1 MANE Select	c.43C>T	p.Leu15Phe	missense	Exon 1 of 27	ENSP00000269571.4	P04626-1
ERBB2	ENST00000584450.5	TSL:1	c.43C>T	p.Leu15Phe	missense	Exon 1 of 26	ENSP00000463714.1	J3QLU9
ERBB2	ENST00000578199.5	TSL:1	c.-18+5100C>T		intron	N/A	ENSP00000462808.1	F5H1T4

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000574

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000783

AC:

AN:

63868

AF XY:

0.000812

show subpopulations

Gnomad AFR exome

AF:

0.000726

Gnomad AMR exome

AF:

0.000518

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000531

GnomAD4 exome

AF:

0.000576

AC:

737

AN:

1280516

Hom.:

Cov.:

AF XY:

0.000626

AC XY:

394

AN XY:

629298

show subpopulations

African (AFR)

AF:

0.0000383

AC:

AN:

26086

American (AMR)

AF:

0.000483

AC:

AN:

22788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21886

East Asian (EAS)

AF:

0.00

AC:

AN:

27914

South Asian (SAS)

AF:

0.00163

AC:

106

AN:

65060

European-Finnish (FIN)

AF:

0.00373

AC:

123

AN:

33002

Middle Eastern (MID)

AF:

0.00107

AC:

AN:

3724

European-Non Finnish (NFE)

AF:

0.000451

AC:

463

AN:

1027294

Other (OTH)

AF:

0.000550

AC:

AN:

52762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

108

144

180

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:

0.000545

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41586

American (AMR)

AF:

0.000196

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000574

AC:

AN:

67968

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.000366

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000599

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.026

MetaSVM

Uncertain

-0.00070

MutationAssessor

Benign

1.4

PhyloP100

3.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.010

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.41

MVP

0.70

MPC

0.37

ClinPred

0.14

GERP RS

2.5

PromoterAI

0.0088

Neutral

(source)

Varity_R

0.17

gMVP

0.18

Mutation Taster

=76/24

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over