rs16937769

Variant names:

• chr10-53809442-T-G
• rs16937769
• ENST00000395445.6:c.4602A>C

Variant summary

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

The NM_001142769.3(PCDH15):​c.4623A>C​(p.Thr1541Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,614,020 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (102 hom.)
• Consequence: PCDH15 NM_001142769.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.41

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=-0.81).
• BP6: Variant 10-53809442-T-G is Benign according to our data. Variant chr10-53809442-T-G is described in ClinVar as [Benign]. Clinvar id is 44033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.4671+1114A>C		intron_variant	Intron 37 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2	c.4671+1114A>C		intron_variant	Intron 37 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1786 AN: 152206 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0599

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00867 AC: 2156 AN: 248800 Hom.: 53 AF XY: 0.00797 AC XY: 1078 AN XY: 135184

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0615

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.00344 AC: 5035 AN: 1461694 Hom.: 102 Cov.: 33 AF XY: 0.00347 AC XY: 2521 AN XY: 727130

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0568

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00765

GnomAD4 genome AF: 0.0118 AC: 1790 AN: 152326 Hom.: 46 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74484

Gnomad4 AFR AF: 0.0308

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0601

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00327 Hom.: 16

Bravo AF: 0.0128

Asia WGS AF: 0.0570 AC: 196 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Sep 14, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr1541Thr in Exon 36 of PCDH15: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 3.2% (77/2374) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs16937769). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.052
DANN	Benign	0.47

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: rs16937769; hg19: chr10-55569202;