rs546886845

Positions:

• chr17-39707009-G-A
• chr17-39707009-G-C
• chr17-39707009-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000578199.5(ERBB2):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000693 in 1,442,178 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ERBB2 ENST00000578199.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.93G>A	p.Met31Ile	missense_variant	2/27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.93G>A	p.Met31Ile	missense_variant	2/27	1	NM_004448.4	ENSP00000269571	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442178 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 716744

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;.;.;.;.;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.9	.;.;.;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	.;.;N;N;.;N;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0080	.;.;D;T;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;T;D;T;D
Polyphen		0.34, 0.31, 0.065	.;B;.;B;.;B;.
Vest4		0.84
MutPred		0.50		.;.;.;.;Loss of ubiquitination at K32 (P = 0.0598);Loss of ubiquitination at K32 (P = 0.0598);.;
MVP		0.97
MPC		0.50
ClinPred		0.72	D
GERP RS		5.2
Varity_R		0.51
gMVP		0.58

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: rs546886845; hg19: chr17-37863262;