dbSNP rs111033463: PCDH15:p.Val1800Ile (chr10-53822328-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033056.4(PCDH15):c.5398G>A(p.Val1800Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,597,250 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00070 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 14 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.93

Publications

10 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 Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
Usher syndrome type 1
Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047968924).

BP6

Variant 10-53822328-C-T is Benign according to our data. Variant chr10-53822328-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000972 (1407/1447634) while in subpopulation SAS AF = 0.00705 (601/85220). AF 95% confidence interval is 0.00659. There are 14 homozygotes in GnomAdExome4. There are 892 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,Unknown gene

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	UniProt
PCDH15	NM_033056.4	MANE Plus Clinical	c.5398G>A	p.Val1800Ile	missense	Exon 33 of 33	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.4368-2098G>A		intron	N/A	NP_001371069.1	Q96QU1-7
PCDH15	NM_001142763.2		c.5419G>A	p.Val1807Ile	missense	Exon 35 of 35	NP_001136235.1	A2A3D8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.5398G>A	p.Val1800Ile	missense	Exon 33 of 33	ENSP00000322604.6	Q96QU1-1
PCDH15	ENST00000644397.2	MANE Select	c.4368-2098G>A		intron	N/A	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000395445.6	TSL:1	c.4388+5065G>A		intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes

AF:

0.000702

AC:

105

AN:

149500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000222

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.000335

Gnomad ASJ

AF:

0.00318

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00466

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000770

Gnomad OTH

AF:

0.00197

GnomAD2 exomes

AF:

0.00138

AC:

304

AN:

221008

AF XY:

0.00177

show subpopulations

Gnomad AFR exome

AF:

0.000488

Gnomad AMR exome

AF:

0.000259

Gnomad ASJ exome

AF:

0.00290

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.000728

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000972

AC:

1407

AN:

1447634

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

892

AN XY:

718994

show subpopulations

African (AFR)

AF:

0.000272

AC:

AN:

33066

American (AMR)

AF:

0.000286

AC:

AN:

41986

Ashkenazi Jewish (ASJ)

AF:

0.00323

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39088

South Asian (SAS)

AF:

0.00705

AC:

601

AN:

85220

European-Finnish (FIN)

AF:

0.0000379

AC:

AN:

52834

Middle Eastern (MID)

AF:

0.00383

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000555

AC:

613

AN:

1103858

Other (OTH)

AF:

0.00107

AC:

AN:

59844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000702

AC:

105

AN:

149616

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

AN XY:

72780

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

40618

American (AMR)

AF:

0.000335

AC:

AN:

14932

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00466

AC:

AN:

4720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000770

AC:

AN:

67524

Other (OTH)

AF:

0.00195

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000927

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00128

AC:

154

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (2)

Usher syndrome type 1F (2)

PCDH15-related disorder (1)

Usher syndrome type 1 (1)

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0040

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.0095

Eigen

Benign

-2.7

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.61

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-3.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.070

REVEL

Benign

0.0070

Sift

Benign

0.70

Sift4G

Benign

0.57

Polyphen

0.0020

Vest4

0.029

MVP

0.19

MPC

0.025

ClinPred

0.00064

GERP RS

-7.5

Varity_R

0.022

gMVP

0.049

Mutation Taster

=99/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over