rs2517960

Variant names:

• chr17-39690268-T-C
• rs2517960
• ENST00000578199.5:c.-277+1468T>C

Variant summary

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

The ENST00000578199.5(ERBB2):​c.-277+1468T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 151,472 control chromosomes in the GnomAD database, including 22,910 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 0.52 (22910 hom., cov: 30)
• Consequence: ERBB2 ENST00000578199.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-283+1468T>C		intron_variant	Intron 2 of 30		NP_001276865.1
ERBB2	NM_001005862.3	c.-277+1468T>C		intron_variant	Intron 2 of 29		NP_001005862.1
ERBB2	NM_001382782.1	c.-584+1468T>C		intron_variant	Intron 2 of 29		NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-277+1468T>C		intron_variant	Intron 2 of 17	1		ENSP00000462808.1
ERBB2	ENST00000584014.5	n.283+1468T>C		intron_variant	Intron 2 of 3	1
ERBB2	ENST00000584601.5	c.-328+1468T>C		intron_variant	Intron 2 of 30	2		ENSP00000462438.1
PGAP3	ENST00000584856.1	c.-35-4249A>G		intron_variant	Intron 1 of 2	4		ENSP00000463785.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78181 AN: 151354 Hom.: 22896 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.543

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.516 AC: 78222 AN: 151472 Hom.: 22910 Cov.: 30 AF XY: 0.517 AC XY: 38262 AN XY: 73972

African (AFR) AF: 0.233 AC: 9630 AN: 41384

American (AMR) AF: 0.531 AC: 8085 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2333 AN: 3458

East Asian (EAS) AF: 0.398 AC: 2040 AN: 5130

South Asian (SAS) AF: 0.692 AC: 3321 AN: 4802

European-Finnish (FIN) AF: 0.674 AC: 7036 AN: 10436

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43795 AN: 67718

Other (OTH) AF: 0.544 AC: 1147 AN: 2110

Alfa AF: 0.549 Hom.: 3215

Bravo AF: 0.490

Asia WGS AF: 0.570 AC: 1981 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2517960; hg19: chr17-37846521; COSMIC: COSV56131599; COSMIC: COSV56131599;