rs74609306

Variant names:

• chr10-53806678-C-T
• rs74609306
• NM_001384140.1:c.5124G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001384140.1(PCDH15):​c.5124G>A​(p.Lys1708Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,613,826 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., cov: 32)
  • Exomes 𝑓: 0.029 (704 hom.)
• Consequence: PCDH15 NM_001384140.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0680

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-53806678-C-T is Benign according to our data. Variant chr10-53806678-C-T is described in ClinVar as [Benign]. Clinvar id is 227004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53806678-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.068 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0196 (2978/152230) while in subpopulation NFE AF= 0.033 (2245/68004). AF 95% confidence interval is 0.0319. There are 36 homozygotes in gnomad4. There are 1370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.5124G>A	p.Lys1708Lys	synonymous_variant	Exon 38 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2	c.5124G>A	p.Lys1708Lys	synonymous_variant	Exon 38 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2976 AN: 152112 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0183

GnomAD3 exomes AF: 0.0192 AC: 4769 AN: 248706 Hom.: 68 AF XY: 0.0190 AC XY: 2562 AN XY: 135132

Gnomad AFR exome AF: 0.00421

Gnomad AMR exome AF: 0.00872

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00539

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0289 AC: 42201 AN: 1461596 Hom.: 704 Cov.: 33 AF XY: 0.0281 AC XY: 20463 AN XY: 727086

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.00919

Gnomad4 ASJ exome AF: 0.00188

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00633

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0342

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0196 AC: 2978 AN: 152230 Hom.: 36 Cov.: 32 AF XY: 0.0184 AC XY: 1370 AN XY: 74440

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.0330

Gnomad4 OTH AF: 0.0181

Alfa AF: 0.0253 Hom.: 37

Bravo AF: 0.0173

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0293

EpiControl AF: 0.0270

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Lys1650Lys in Exon 37 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 2.8% (154/5446) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs74609306). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs74609306; hg19: chr10-55566438;