10-53806646-T-G

Position:

• chr10-53806646-T-G

Variant summary

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

The NM_001384140.1(PCDH15):​c.5156A>C​(p.Gln1719Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,326 control chromosomes in the GnomAD database, including 63,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3936 hom., cov: 32)
  • Exomes 𝑓: 0.27 (59845 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.58

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 (MetaRNN=0.004988849).
• BP6: Variant 10-53806646-T-G is Benign according to our data. Variant chr10-53806646-T-G is described in ClinVar as [Benign]. Clinvar id is 227005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.5156A>C	p.Gln1719Pro	missense_variant	38/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000644397.2	c.5156A>C	p.Gln1719Pro	missense_variant	38/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30172 AN: 151958 Hom.: 3939 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.212 AC: 52654 AN: 248680 Hom.: 6905 AF XY: 0.218 AC XY: 29411 AN XY: 135114

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.00134

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.275 AC: 401654 AN: 1461250 Hom.: 59845 Cov.: 35 AF XY: 0.273 AC XY: 198384 AN XY: 726934

Gnomad4 AFR exome AF: 0.0476

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.243

GnomAD4 genome AF: 0.198 AC: 30160 AN: 152076 Hom.: 3936 Cov.: 32 AF XY: 0.193 AC XY: 14360 AN XY: 74336

Gnomad4 AFR AF: 0.0560

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.200

Alfa AF: 0.263 Hom.: 9144

Bravo AF: 0.182

TwinsUK AF: 0.307 AC: 1137

ALSPAC AF: 0.292 AC: 1125

ESP6500AA AF: 0.0609 AC: 191

ESP6500EA AF: 0.295 AC: 2114

ExAC AF: 0.212 AC: 25570

Asia WGS AF: 0.0830 AC: 291 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.289

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1F Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 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

Gln1661Pro in Exon 37 of PCDH15: This variant is not expected to have clinical s ignificance because it has been identified in 29.7% (1617/5446) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs17704703). -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.020	T;.;.;.;.;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
REVEL	Benign	0.039
Sift4G	Benign	0.083	T;.;T;T;T;T;T;T
Vest4		0.18
ClinPred		0.0056	T
GERP RS		3.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17704703; hg19: chr10-55566406;