chr10-54189391-G-A

Position:

• chr10-54189391-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000395445.6(PCDH15):​c.1306-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,522,380 control chromosomes in the GnomAD database, including 36,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3757 hom., cov: 32)
  • Exomes 𝑓: 0.17 (32391 hom.)
• Consequence: PCDH15 ENST00000395445.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0009823
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.18

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 10-54189391-G-A is Benign according to our data. Variant chr10-54189391-G-A is described in ClinVar as [Benign]. Clinvar id is 44031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.1306-4123C>T		intron_variant		ENST00000644397.2	NP_001371069.1
PCDH15	NM_033056.4	c.1306-4123C>T		intron_variant		ENST00000320301.11	NP_149045.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1306-4123C>T		intron_variant		1	NM_033056.4	ENSP00000322604
PCDH15	ENST00000644397.2	c.1306-4123C>T		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26488 AN: 151684 Hom.: 3756 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.235 AC: 40068 AN: 170490 Hom.: 7697 AF XY: 0.237 AC XY: 21573 AN XY: 91120

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.841

Gnomad SAS exome AF: 0.349

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.172 AC: 235065 AN: 1370578 Hom.: 32391 Cov.: 27 AF XY: 0.176 AC XY: 119500 AN XY: 678250

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.269

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.869

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.175 AC: 26498 AN: 151802 Hom.: 3757 Cov.: 32 AF XY: 0.185 AC XY: 13707 AN XY: 74180

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.842

Gnomad4 SAS AF: 0.369

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.178

Alfa AF: 0.143 Hom.: 2404

Bravo AF: 0.181

Asia WGS AF: 0.572 AC: 1976 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
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

1321-7C>T in Intron 12 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 12.6% (685/5434) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs16905686). -

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	-0.41
CADD	Benign	13
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00098
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.010		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: rs16905686; hg19: chr10-55949151;