chr10-54317272-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033056.4(PCDH15):c.875C>G(p.Pro292Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P292L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense, splice_region

Scores

Splicing: ADA: 0.9243

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.77

Publications

5 publications found

Variant links:

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]

PCDH15 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 8 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 8 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 8 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 8 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251218

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460086

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1110460

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1F

Uncertain:2

Apr 16, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Pro292Arg variant in PCDH15 has been reported in 1 individual with Usher syndrome type 1F (PMID: 24498627) and has been identified in 0.0009% (1/113578) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs138744579). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 557886) and has been interpreted as a variant of uncertain significance by Counsyl and CeGaT Center for Human Genetics Tuebingen. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro292Arg variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015). -

not provided

Uncertain:1

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;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

0.071

MetaRNN

Uncertain

0.71

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.6

.;.;.;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;M;M

PhyloP100

9.8

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.1

D;.;.;D;.;.;D;D;.;D;.;D;D;.;D;.;.;D;D;D;.;D;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.038

D;.;.;D;.;.;D;D;.;D;.;T;D;.;D;.;.;D;D;T;.;T;D;D

Sift4G

Uncertain

0.0050

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0, 1.0, 1.0, 0.91

.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;D;.;D;D;P

Vest4

0.90

MutPred

0.28

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;.;.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.86

MPC

0.23

ClinPred

0.99

GERP RS

4.8

Varity_R

0.54

gMVP

0.66

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over