17-39699581-C-A

Position:

• chr17-39699581-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_001289936.2(ERBB2):​c.22C>A​(p.Pro8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,516,162 control chromosomes in the GnomAD database, including 12,340 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.087 (821 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11519 hom.)
• Consequence: ERBB2 NM_001289936.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.0150

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 -11 ACMG points.

• 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 4.4427 (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=0.001347214).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.22C>A	p.Pro8Thr	missense_variant	5/31		NP_001276865.1
ERBB2	XM_047435590.1	c.22C>A	p.Pro8Thr	missense_variant	6/32		XP_047291546.1
ERBB2	NM_001005862.3	c.-18+4400C>A		intron_variant			NP_001005862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+4400C>A		intron_variant		1		ENSP00000462808.1
ERBB2	ENST00000541774.5	c.22C>A	p.Pro8Thr	missense_variant	1/27	5		ENSP00000446466.1
ERBB2	ENST00000584601	c.-24C>A		5_prime_UTR_variant	5/31	2		ENSP00000462438.1
ERBB2	ENST00000406381.6	c.-18+4400C>A		intron_variant		5		ENSP00000385185.2

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13284 AN: 152102 Hom.: 821 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0632

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0680

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.108 AC: 13903 AN: 128144 Hom.: 1054 AF XY: 0.120 AC XY: 8421 AN XY: 70196

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0427

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.000767

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.0663

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.123 AC: 167613 AN: 1363942 Hom.: 11519 Cov.: 26 AF XY: 0.126 AC XY: 85144 AN XY: 674070

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.0473

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.000616

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0731

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.0872 AC: 13280 AN: 152220 Hom.: 821 Cov.: 32 AF XY: 0.0835 AC XY: 6215 AN XY: 74418

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.0631

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.0680

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.0758

Alfa AF: 0.124 Hom.: 1345

Bravo AF: 0.0801

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.127 AC: 489

ExAC AF: 0.143 AC: 2006

Asia WGS AF: 0.0630 AC: 224 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.2
DANN	Benign	0.87
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	0.61	N
REVEL	Benign	0.071
Sift	Benign	0.81	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.039
ClinPred		0.0063	T
GERP RS		-2.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4252596; hg19: chr17-37855834; COSMIC: COSV54064965; COSMIC: COSV54064965;