17-39727704-C-T

Position:

chr17-39727704-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBS1_Supporting

The NM_004448.4(ERBB2):c.3428C>T(p.Pro1143Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,402,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ERBB2
NM_004448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.283

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 links:

ERBB2 (HGNC:):

ERBB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERBB2. . Gene score misZ 3.2497 (greater than the threshold 3.09). Trascript score misZ 4.234 (greater than threshold 3.09). GenCC has associacion of gene with visceral neuropathy, familial, 2, autosomal recessive, lung cancer, Hirschsprung disease, glioma susceptibility 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.027276695).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000114 (16/1402416) while in subpopulation SAS AF= 0.000206 (16/77732). AF 95% confidence interval is 0.000128. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4 linkuse as main transcript	c.3428C>T	p.Pro1143Leu	missense_variant	27/27	ENST00000269571.10	NP_004439.2	P04626-1X5DNK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10 linkuse as main transcript	c.3428C>T	p.Pro1143Leu	missense_variant	27/27	1	NM_004448.4	ENSP00000269571.4		P04626-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000981

AC:

AN:

203916

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

109122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1402416

Hom.:

Cov.:

AF XY:

0.0000202

AC XY:

AN XY:

692162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 134081). This variant has not been reported in the literature in individuals affected with ERBB2-related conditions. This variant is present in population databases (rs587778269, gnomAD 0.009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1143 of the ERBB2 protein (p.Pro1143Leu). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.24

.;.;.;T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.76

.;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;.;.;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.26

.;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.31

.;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.017, 0.0010

.;.;B;B;B

Vest4

0.055

MutPred

0.15

.;.;.;.;Loss of relative solvent accessibility (P = 0.0981);

MVP

0.75

MPC

0.35

ClinPred

0.036

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over