rs77290854

Positions:

• chr10-54528370-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033056.4(PCDH15):​c.92-493A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,568,094 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (19 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.293

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-54528370-T-A is Benign according to our data. Variant chr10-54528370-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 445899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54528370-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00823 (1252/152134) while in subpopulation AFR AF= 0.0284 (1180/41554). AF 95% confidence interval is 0.0271. There are 16 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.92-493A>T		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.92-493A>T		intron_variant		ENST00000320301.11
LOC105378311	NR_134503.1	n.88-40195T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.92-493A>T		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.92-493A>T		intron_variant			NM_001384140.1
	ENST00000422842.1	n.88-40195T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1250 AN: 152016 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00197 AC: 379 AN: 192076 Hom.: 6 AF XY: 0.00161 AC XY: 165 AN XY: 102308

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000864

Gnomad OTH exome AF: 0.000399

GnomAD4 exome AF: 0.000833 AC: 1179 AN: 1415960 Hom.: 19 Cov.: 30 AF XY: 0.000728 AC XY: 510 AN XY: 701008

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00169

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000867

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000194

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00823 AC: 1252 AN: 152134 Hom.: 16 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74384

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00453 Hom.: 1

Bravo AF: 0.00967

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77290854; hg19: chr10-56288130;