rs375855445

Positions:

• chr10-54022994-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384140.1(PCDH15):​c.2424G>C​(p.Lys808Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.282

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057411432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.2424G>C	p.Lys808Asn	missense_variant	19/33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.2424G>C	p.Lys808Asn	missense_variant	19/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.2424G>C	p.Lys808Asn	missense_variant	19/33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.2424G>C	p.Lys808Asn	missense_variant	19/38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.000177

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 251326 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 236 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74280

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2024	Identified in a cohort of individuals with syndromic and nonsyndromic blindness (PMID: 32483926); patient clinical information not provided; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 15537665) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2015	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2016	- -

Usher syndrome type 1F Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;.;.;.;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	.;.;.;.;.;.;.;N;.;N;N;.;N;.;.;N;N;N;.;N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.021	.;.;.;.;.;.;.;D;.;D;T;.;T;.;.;T;T;T;.;T;T;D
Sift4G	Uncertain	0.024	D;.;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;T
Polyphen		0.26, 0.74, 0.18, 0.99, 0.74, 0.045, 0.0040	.;.;.;.;.;.;.;.;.;.;B;.;P;.;.;B;D;D;.;P;B;B
Vest4		0.66
MutPred		0.55		Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;Loss of ubiquitination at K808 (P = 0.0224);.;.;.;Loss of ubiquitination at K808 (P = 0.0224);.;.;.;.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);.;.;.;Loss of ubiquitination at K808 (P = 0.0224);Loss of ubiquitination at K808 (P = 0.0224);
MVP		0.60
MPC		0.039
ClinPred		0.064	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.45

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: rs375855445; hg19: chr10-55782754;