rs202125339

Positions:

• chr10-54183422-CTTATA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):​c.1590+17_1590+21del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000717 in 1,591,132 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 10-54183422-CTTATA-C is Benign according to our data. Variant chr10-54183422-CTTATA-C is described in ClinVar as [Benign]. Clinvar id is 164926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54183422-CTTATA-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00393 (598/152306) while in subpopulation AFR AF= 0.0138 (573/41568). AF 95% confidence interval is 0.0129. There are 3 homozygotes in gnomad4. There are 279 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.1590+17_1590+21del		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.1590+17_1590+21del		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.1590+17_1590+21del		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.1590+17_1590+21del		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 257 AN: 251162 Hom.: 1 AF XY: 0.000729 AC XY: 99 AN XY: 135754

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000377 AC: 543 AN: 1438826 Hom.: 2 AF XY: 0.000312 AC XY: 224 AN XY: 717306

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000385

Gnomad4 OTH exome AF: 0.000805

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00375 AC XY: 279 AN XY: 74466

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00243 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2015

1590+15_1590+19del in intron 13 of PCDH15: This variant is not expected to have clinical significance because it is not located within the splice consensus sequ ence and has been identified in 7.3% (14/192) of LWK (Kenyan) chromosomes by the 1000 Genomes Project (dbSNP rs202125339). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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: rs202125339; hg19: chr10-55943182;