rs7093302

Positions:

• chr10-54183424-T-C
• chr10-54183424-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.1590+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,589,456 control chromosomes in the GnomAD database, including 412,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42942 hom., cov: 34)
  • Exomes 𝑓: 0.71 (369295 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.62

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: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-54183424-T-C is Benign according to our data. Variant chr10-54183424-T-C is described in ClinVar as [Benign]. Clinvar id is 262145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54183424-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.1590+20A>G		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.1590+20A>G		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1590+20A>G		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.1590+20A>G		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.739 AC: 112319 AN: 151900 Hom.: 42891 Cov.: 34

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.755

GnomAD3 exomes AF: 0.661 AC: 165986 AN: 251122 Hom.: 58487 AF XY: 0.660 AC XY: 89565 AN XY: 135746

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.760

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.555

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.703

GnomAD4 exome AF: 0.707 AC: 1016282 AN: 1437440 Hom.: 369295 Cov.: 31 AF XY: 0.703 AC XY: 504028 AN XY: 716668

Gnomad4 AFR exome AF: 0.858

Gnomad4 AMR exome AF: 0.624

Gnomad4 ASJ exome AF: 0.762

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.559

Gnomad4 FIN exome AF: 0.714

Gnomad4 NFE exome AF: 0.738

Gnomad4 OTH exome AF: 0.698

GnomAD4 genome AF: 0.740 AC: 112426 AN: 152016 Hom.: 42942 Cov.: 34 AF XY: 0.730 AC XY: 54236 AN XY: 74332

Gnomad4 AFR AF: 0.847

Gnomad4 AMR AF: 0.708

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.744

Gnomad4 OTH AF: 0.751

Alfa AF: 0.738 Hom.: 50962

Bravo AF: 0.742

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The variant of interest is located a non-conserved intronic position, not widely known to affect splicing, with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 80522/121302 (including 28510 homozygotes), which indicates that the variant of interest is the major allele (most commonly found in the general population). In addition, a reputable clinical laboratory cites the variant with a classification of "benign." Therefore, the variant of interest is classified as Benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Usher syndrome type 1F Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.36

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: rs7093302; hg19: chr10-55943184; COSMIC: COSV57418326;