rs1196401374

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_033056.4(PCDH15):c.1456G>C(p.Gly486Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G486S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81

Publications

3 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.1456G>C	p.Gly486Arg	missense_variant	Exon 13 of 33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.1456G>C	p.Gly486Arg	missense_variant	Exon 13 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.1456G>C	p.Gly486Arg	missense_variant	Exon 13 of 33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.1456G>C	p.Gly486Arg	missense_variant	Exon 13 of 38		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251298

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111938

Other (OTH)

AF:

0.00

AC:

AN:

60390

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

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:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1456G>C (p.G486R) alteration is located in exon 13 (coding exon 12) of the PCDH15 gene. This alteration results from a G to C substitution at nucleotide position 1456, causing the glycine (G) at amino acid position 486 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.086

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

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

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

Uncertain

0.15

MetaRNN

Pathogenic

0.81

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

-0.28

MutationAssessor

Uncertain

2.3

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

PhyloP100

7.8

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

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

Sift4G

Pathogenic

0.0

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

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

Vest4

0.92

MutPred

0.46

Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);.;Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);.;Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);.;.;.;Gain of solvent accessibility (P = 0.0471);.;.;.;Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);.;.;Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);Gain of solvent accessibility (P = 0.0471);

MVP

0.91

MPC

0.24

ClinPred

0.98

GERP RS

5.3

Varity_R

0.40

gMVP

0.73

Mutation Taster

=15/85

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over