Genetic Variant PCDH15:p.Thr1620Thr (chr10-53806942-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001384140.1(PCDH15):c.4860G>A(p.Thr1620Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,613,760 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 14 hom. )

Consequence

PCDH15
NM_001384140.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.79

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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 10-53806942-C-T is Benign according to our data. Variant chr10-53806942-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00422 (6174/1461648) while in subpopulation NFE AF = 0.00514 (5711/1111822). AF 95% confidence interval is 0.00503. There are 14 homozygotes in GnomAdExome4. There are 3044 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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_001384140.1	MANE Select	c.4860G>A	p.Thr1620Thr	synonymous	Exon 38 of 38	NP_001371069.1	Q96QU1-7
PCDH15	NM_001354429.2		c.4794G>A	p.Thr1598Thr	synonymous	Exon 37 of 37	NP_001341358.1
PCDH15	NM_001142771.2		c.4686G>A	p.Thr1562Thr	synonymous	Exon 36 of 36	NP_001136243.1	A0A087X1T6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH15	ENST00000644397.2	MANE Select	c.4860G>A	p.Thr1620Thr	synonymous	Exon 38 of 38	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000616114.4	TSL:1	c.4665G>A	p.Thr1555Thr	synonymous	Exon 34 of 34	ENSP00000483745.1	Q96QU1-6
PCDH15	ENST00000621708.4	TSL:5	c.4686G>A	p.Thr1562Thr	synonymous	Exon 36 of 36	ENSP00000484454.1	A0A087X1T6

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

412

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00264

AC:

655

AN:

248464

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.000972

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00445

Gnomad OTH exome

AF:

0.00397

GnomAD4 exome

AF:

0.00422

AC:

6174

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

3044

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33474

American (AMR)

AF:

0.00250

AC:

112

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00115

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00514

AC:

5711

AN:

1111822

Other (OTH)

AF:

0.00292

AC:

176

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

387

774

1161

1548

1935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.00271

AC:

412

AN:

152112

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

196

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

41508

American (AMR)

AF:

0.00334

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00460

AC:

313

AN:

67988

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

116

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:

0.00311

Hom.:

Bravo

AF:

0.00255

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00584

EpiControl

AF:

0.00338

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.019

(source)

DANN

Benign

0.32

PhyloP100

-2.8

Mutation Taster

=97/3

polymorphism

(source)

Splicing

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