17-39715782-G-T

Position:

• chr17-39715782-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_004448.4(ERBB2):​c.1356G>T​(p.Trp452Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,608,802 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ERBB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.007810861).
• BP6: Variant 17-39715782-G-T is Benign according to our data. Variant chr17-39715782-G-T is described in ClinVar as [Benign]. Clinvar id is 134072.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2118/152324) while in subpopulation AFR AF= 0.0484 (2011/41572). AF 95% confidence interval is 0.0466. There are 56 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERBB2	NM_004448.4	c.1356G>T	p.Trp452Cys	missense_variant	12/27	ENST00000269571.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERBB2	ENST00000269571.10	c.1356G>T	p.Trp452Cys	missense_variant	12/27	1	NM_004448.4	P1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2109 AN: 152206 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00373 AC: 921 AN: 247046 Hom.: 14 AF XY: 0.00264 AC XY: 354 AN XY: 133970

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00129 AC: 1872 AN: 1456478 Hom.: 39 Cov.: 32 AF XY: 0.00113 AC XY: 817 AN XY: 724840

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.0139 AC: 2118 AN: 152324 Hom.: 56 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74492

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00230 Hom.: 9

Bravo AF: 0.0157

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00445 AC: 540

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	Uncertain	0.49
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Benign	0.88
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.48	N
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	0.80	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D
Polyphen		0.98, 0.96, 0.95, 0.90	.;D;.;D;P;.;P
Vest4		0.41
MutPred		0.41		.;.;.;.;.;Gain of phosphorylation at S457 (P = 0.1782);Gain of phosphorylation at S457 (P = 0.1782);
MVP		0.81
MPC		1.3
ClinPred		0.049	T
GERP RS		2.8
Varity_R		0.38
gMVP		0.79

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

Other links and lift over

dbSNP: rs4252633; hg19: chr17-37872035; COSMIC: COSV99068611; COSMIC: COSV99068611;