rs2643195

Variant names:

• chr17-39696865-A-G
• rs2643195
• ENST00000578199.5:c.-18+1684A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000578199.5(ERBB2):​c.-18+1684A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,044 control chromosomes in the GnomAD database, including 27,492 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.

• Frequency:
  • Genomes: 𝑓 0.58 (27458 hom., cov: 30)
  • Exomes 𝑓: 0.57 (34 hom.)
• Consequence: ERBB2 ENST00000578199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.858
• Publications: 15 publications found

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]

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-24+1684A>G		intron_variant	Intron 4 of 30		NP_001276865.1
ERBB2	NM_001005862.3	c.-18+1684A>G		intron_variant	Intron 4 of 29		NP_001005862.1
ERBB2	NM_001382782.1	c.-18+1684A>G		intron_variant	Intron 4 of 29		NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+1684A>G		intron_variant	Intron 4 of 17	1		ENSP00000462808.1
ERBB2	ENST00000406381.6	c.-18+1684A>G		intron_variant	Intron 1 of 26	5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-69+1684A>G		intron_variant	Intron 4 of 30	2		ENSP00000462438.1
PGAP3	ENST00000584856.1	c.-395T>C		upstream_gene_variant		4		ENSP00000463785.1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88485 AN: 151730 Hom.: 27435 Cov.: 30

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.732

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.571 AC: 112 AN: 196 Hom.: 34 AF XY: 0.636 AC XY: 84 AN XY: 132

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 4 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.500 AC: 5 AN: 10

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 15 AN: 30

Middle Eastern (MID) AF: 0.750 AC: 3 AN: 4

European-Non Finnish (NFE) AF: 0.612 AC: 82 AN: 134

Other (OTH) AF: 0.250 AC: 2 AN: 8

GnomAD4 genome AF: 0.583 AC: 88548 AN: 151848 Hom.: 27458 Cov.: 30 AF XY: 0.583 AC XY: 43275 AN XY: 74172

African (AFR) AF: 0.376 AC: 15559 AN: 41366

American (AMR) AF: 0.573 AC: 8756 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2449 AN: 3470

East Asian (EAS) AF: 0.399 AC: 2052 AN: 5144

South Asian (SAS) AF: 0.733 AC: 3531 AN: 4814

European-Finnish (FIN) AF: 0.708 AC: 7450 AN: 10520

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46573 AN: 67942

Other (OTH) AF: 0.594 AC: 1256 AN: 2116

Alfa AF: 0.659 Hom.: 94107

Bravo AF: 0.558

Asia WGS AF: 0.623 AC: 2168 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.82
DANN	Benign	0.81
PhyloP100		-0.86
PromoterAI		0.015	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2643195; hg19: chr17-37853118;