rs116339167

Positions:

• chr10-54236960-C-A

Variant summary

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

The NM_001384140.1(PCDH15):​c.877-29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,526,374 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.014 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (52 hom.)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.538

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 -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-54236960-C-A is Benign according to our data. Variant chr10-54236960-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 262151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54236960-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2186/152152) while in subpopulation AFR AF= 0.0448 (1859/41518). AF 95% confidence interval is 0.0431. There are 33 homozygotes in gnomad4. There are 1019 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.877-29G>T		intron_variant		ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.877-29G>T		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.877-29G>T		intron_variant		1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.877-29G>T		intron_variant			NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2184 AN: 152034 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00492 AC: 1235 AN: 251146 Hom.: 23 AF XY: 0.00402 AC XY: 546 AN XY: 135742

Gnomad AFR exome AF: 0.0454

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00267 AC: 3664 AN: 1374222 Hom.: 52 Cov.: 23 AF XY: 0.00251 AC XY: 1729 AN XY: 689182

Gnomad4 AFR exome AF: 0.0475

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000592

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.0144 AC: 2186 AN: 152152 Hom.: 33 Cov.: 33 AF XY: 0.0137 AC XY: 1019 AN XY: 74400

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0118 Hom.: 3

Bravo AF: 0.0166

Asia WGS AF: 0.00404 AC: 14 AN: 3478

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.65
DANN	Benign	0.71
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs116339167; hg19: chr10-55996720;