rs61731389

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001142763.2(PCDH15):c.1925A>G(p.Asn642Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0271 in 1,612,316 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 86 hom., cov: 32)

Exomes 𝑓: 0.027 ( 705 hom. )

Consequence

PCDH15
NM_001142763.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.18

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009124845).

BP6

Variant 10-54132882-T-C is Benign according to our data. Variant chr10-54132882-T-C is described in ClinVar as Benign. ClinVar VariationId is 46448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142763.2. 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.1910A>G	p.Asn637Ser	missense	Exon 15 of 33	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.1910A>G	p.Asn637Ser	missense	Exon 15 of 38	NP_001371069.1
PCDH15	NM_001142763.2		c.1925A>G	p.Asn642Ser	missense	Exon 16 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.1910A>G	p.Asn637Ser	missense	Exon 15 of 33	ENSP00000322604.6
PCDH15	ENST00000644397.2	MANE Select	c.1910A>G	p.Asn637Ser	missense	Exon 15 of 38	ENSP00000495195.1
PCDH15	ENST00000395445.6	TSL:1	c.1931A>G	p.Asn644Ser	missense	Exon 16 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4487

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0356

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0487

Gnomad FIN

AF:

0.0270

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0275

AC:

6832

AN:

248534

AF XY:

0.0290

show subpopulations

Gnomad AFR exome

AF:

0.0370

Gnomad AMR exome

AF:

0.0174

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.00205

Gnomad FIN exome

AF:

0.0238

Gnomad NFE exome

AF:

0.0274

Gnomad OTH exome

AF:

0.0344

GnomAD4 exome

AF:

0.0269

AC:

39249

AN:

1460236

Hom.:

705

Cov.:

AF XY:

0.0277

AC XY:

20129

AN XY:

726292

show subpopulations

African (AFR)

AF:

0.0367

AC:

1225

AN:

33406

American (AMR)

AF:

0.0179

AC:

798

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.0347

AC:

905

AN:

26098

East Asian (EAS)

AF:

0.00104

AC:

AN:

39566

South Asian (SAS)

AF:

0.0496

AC:

4271

AN:

86024

European-Finnish (FIN)

AF:

0.0238

AC:

1270

AN:

53346

Middle Eastern (MID)

AF:

0.0709

AC:

409

AN:

5766

European-Non Finnish (NFE)

AF:

0.0256

AC:

28491

AN:

1111100

Other (OTH)

AF:

0.0305

AC:

1839

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

2203

4407

6610

8814

11017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1038

2076

3114

4152

5190

<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:

0.0295

AC:

4491

AN:

152080

Hom.:

Cov.:

AF XY:

0.0303

AC XY:

2256

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0356

AC:

1478

AN:

41488

American (AMR)

AF:

0.0279

AC:

426

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5164

South Asian (SAS)

AF:

0.0489

AC:

236

AN:

4822

European-Finnish (FIN)

AF:

0.0270

AC:

286

AN:

10592

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0270

AC:

1832

AN:

67952

Other (OTH)

AF:

0.0393

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0281

Hom.:

247

Bravo

AF:

0.0291

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.0365

AC:

161

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0280

AC:

3396

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Usher syndrome type 1F (2)

Autosomal recessive nonsyndromic hearing loss 23 (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

PhyloP100

6.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

REVEL

Benign

0.17

Sift

Benign

0.50

Sift4G

Uncertain

0.028

Polyphen

0.95

Vest4

0.69

MPC

0.070

ClinPred

0.089

GERP RS

3.2

Varity_R

0.15

gMVP

0.31

Mutation Taster

=95/5

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over