rs727503363

Positions:

• chr10-53822448-GAGGAGGAGA-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_033056.4(PCDH15):​c.5269_5277del​(p.Ser1757_Pro1759del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00058 in 1,597,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1757S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: PCDH15 NM_033056.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.32

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 10-53822448-GAGGAGGAGA-G is Benign according to our data. Variant chr10-53822448-GAGGAGGAGA-G is described in ClinVar as [Likely_benign]. Clinvar id is 164903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.5269_5277del	p.Ser1757_Pro1759del	inframe_deletion	33/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.4368-2227_4368-2219del		intron_variant		ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.5269_5277del	p.Ser1757_Pro1759del	inframe_deletion	33/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.4368-2227_4368-2219del		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.000298 AC: 45 AN: 151224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000343 AC: 76 AN: 221474 Hom.: 0 AF XY: 0.000357 AC XY: 43 AN XY: 120456

Gnomad AFR exome AF: 0.000301

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000124

Gnomad SAS exome AF: 0.0000697

Gnomad FIN exome AF: 0.0000492

Gnomad NFE exome AF: 0.000630

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.000609 AC: 881 AN: 1445732 Hom.: 0 AF XY: 0.000581 AC XY: 417 AN XY: 718148

Gnomad4 AFR exome AF: 0.000650

Gnomad4 AMR exome AF: 0.0000697

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000157

Gnomad4 SAS exome AF: 0.0000946

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.000706

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000297 AC: 45 AN: 151340 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 73978

Gnomad4 AFR AF: 0.000294

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

Ser1757_Pro1759del in exon 33 of PCDH15: This variant is not expected to have c linical significance because it has been identified in 0.12% (10/8244) of Europe an American chromosomes and 0.58% (25/4260) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503363; hg19: chr10-55582208;