rs7090408

Positions:

• chr10-53808829-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The ENST00000395445.6(PCDH15):​c.5215G>A​(p.Gly1739Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,610,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: PCDH15 ENST00000395445.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.189

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036241412).
• BP6: Variant 10-53808829-C-T is Benign according to our data. Variant chr10-53808829-C-T is described in ClinVar as [Benign]. Clinvar id is 44036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53808829-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00211 (321/152224) while in subpopulation AFR AF= 0.00715 (297/41542). AF 95% confidence interval is 0.00648. There are 0 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1	c.4672-1699G>A		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2	c.4672-1699G>A		intron_variant			NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000581 AC: 141 AN: 242850 Hom.: 0 AF XY: 0.000372 AC XY: 49 AN XY: 131686

Gnomad AFR exome AF: 0.00807

Gnomad AMR exome AF: 0.000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000181 AC: 264 AN: 1458524 Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 99 AN XY: 725054

Gnomad4 AFR exome AF: 0.00595

Gnomad4 AMR exome AF: 0.000407

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74422

Gnomad4 AFR AF: 0.00715

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000359 Hom.: 0

Bravo AF: 0.00249

ESP6500AA AF: 0.00829 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000763 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2017

Gly1746Ser in Exon 37A of PCDH15: This variant is not expected to have clinical significance because it has been identified in 0.7% (164/23056) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs7090408). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.46
DANN	Benign	0.66
DEOGEN2	Benign	0.0031	.;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.64	T;T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.29	N;N;N;.;.;.
REVEL	Benign	0.078
Sift	Benign	0.93	T;T;T;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Vest4		0.16
MVP		0.15
ClinPred		0.0018	T
GERP RS		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs7090408; hg19: chr10-55568589;