rs149867749

Positions:

• chr10-53840308-A-G

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.3983+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,613,324 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (46 hom.)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.459

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=-0.85).
• BP6: Variant 10-53840308-A-G is Benign according to our data. Variant chr10-53840308-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53840308-A-G is described in Lovd as [Likely_benign]. Variant chr10-53840308-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00471 (718/152350) while in subpopulation NFE AF= 0.00779 (530/68032). AF 95% confidence interval is 0.00724. There are 7 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.3983+12T>C		intron_variant		ENST00000644397.2
PCDH15	NM_033056.4	c.3983+12T>C		intron_variant		ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3983+12T>C		intron_variant		1	NM_033056.4
PCDH15	ENST00000644397.2	c.3983+12T>C		intron_variant			NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152232 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00499 AC: 1254 AN: 251440 Hom.: 8 AF XY: 0.00514 AC XY: 699 AN XY: 135888

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00783

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00633 AC: 9251 AN: 1460974 Hom.: 46 Cov.: 31 AF XY: 0.00627 AC XY: 4554 AN XY: 726880

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00244

Gnomad4 FIN exome AF: 0.00769

Gnomad4 NFE exome AF: 0.00729

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00471 AC: 718 AN: 152350 Hom.: 7 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74504

Gnomad4 AFR AF: 0.000817

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00687 Hom.: 1

Bravo AF: 0.00420

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	3983+12T>C in Intron 29 of PCDH15: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.7% (46/7020) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs149867749). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 16, 2018	Variant summary: PCDH15 c.3983+12T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0052 in 277196 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is benign. c.3983+12T>C has been reported in the literature in individuals affected with Usher Syndrome Type 1F. These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. However, two other clinical diagnostic laboratories classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 21, 2022

- -

Usher syndrome type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.0
DANN	Benign	0.56

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: rs149867749; hg19: chr10-55600068;