10-54527841-A-G

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.128T>C(p.Ile43Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,611,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.62

Publications

0 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:

ENSG00000234173 (HGNC:):

ENSG00000234173 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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCDH15	NM_033056.4	MANE Plus Clinical	c.128T>C	p.Ile43Thr	missense	Exon 3 of 33	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.128T>C	p.Ile43Thr	missense	Exon 3 of 38	NP_001371069.1
PCDH15	NM_001142763.2		c.143T>C	p.Ile48Thr	missense	Exon 4 of 35	NP_001136235.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.128T>C	p.Ile43Thr	missense	Exon 3 of 33	ENSP00000322604.6
PCDH15	ENST00000644397.2	MANE Select	c.128T>C	p.Ile43Thr	missense	Exon 3 of 38	ENSP00000495195.1
PCDH15	ENST00000395445.6	TSL:1	c.128T>C	p.Ile43Thr	missense	Exon 3 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250986

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1459788

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726212

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33422

American (AMR)

AF:

0.0000224

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1110516

Other (OTH)

AF:

0.00

AC:

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67948

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jul 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2

Dec 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 43 of the PCDH15 protein (p.Ile43Thr). This variant is present in population databases (rs766772151, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 229132). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not specified

Uncertain:1

Jul 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ile43Thr variant in PCDH15 has not been previously reported in individuals with hearing loss, but has been identified in 2/66624 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs7 66772151). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Ile43Thr variant is uncertain.

Usher syndrome type 1F

Uncertain:1

Nov 11, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.90

PhyloP100

7.6

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.92

Vest4

0.88

MVP

0.75

MPC

0.16

ClinPred

0.93

GERP RS

5.7

Varity_R

0.49

gMVP

0.83

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over