rs1058808

Positions:

• chr17-39727784-C-A
• chr17-39727784-C-G
• chr17-39727784-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004448.4(ERBB2):​c.3508C>A​(p.Pro1170Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,340 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1170A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (1 hom.)
• Consequence: ERBB2 NM_004448.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.29

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. 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=0.30468026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_004448.4	c.3508C>A	p.Pro1170Thr	missense_variant	27/27	ENST00000269571.10	NP_004439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000269571.10	c.3508C>A	p.Pro1170Thr	missense_variant	27/27	1	NM_004448.4	ENSP00000269571.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460340 Hom.: 1 Cov.: 52 AF XY: 0.00000275 AC XY: 2 AN XY: 726276

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: 0.0000232

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	Benign	0.090
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;T;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Benign	0.69	.;.;.;.;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	.;N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0090	.;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;T;D
Polyphen		0.87, 0.99, 0.99	.;.;P;D;D
Vest4		0.53
MutPred		0.20		.;.;.;.;Gain of phosphorylation at P1170 (P = 0.0424);
MVP		0.63
MPC		1.1
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1058808; hg19: chr17-37884037;