Genetic Variant PCDH15:c.3718-19C>A (chr10-53857282-G-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_001384140.1(PCDH15):c.3718-19C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,582,082 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 47 hom., cov: 31)

Exomes 𝑓: 0.026 ( 553 hom. )

Consequence

PCDH15
NM_001384140.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.226

Publications

2 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 (BayesDel_noAF=-0.85).

BP6

Variant 10-53857282-G-T is Benign according to our data. Variant chr10-53857282-G-T is described in ClinVar as Benign. ClinVar VariationId is 46472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0219 (3318/151816) while in subpopulation SAS AF = 0.0383 (184/4798). AF 95% confidence interval is 0.0338. There are 47 homozygotes in GnomAd4. There are 1571 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 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	Effect	Exon Rank	Protein	UniProt
PCDH15	NM_033056.4	MANE Plus Clinical	c.3718-19C>A	intron	N/A	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.3718-19C>A	intron	N/A	NP_001371069.1	Q96QU1-7
PCDH15	NM_001142763.2		c.3733-19C>A	intron	N/A	NP_001136235.1	A2A3D8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3718-19C>A	intron	N/A	ENSP00000322604.6	Q96QU1-1
PCDH15	ENST00000644397.2	MANE Select	c.3718-19C>A	intron	N/A	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000395445.6	TSL:1	c.3739-19C>A	intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3309

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0152

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.0298

Gnomad EAS

AF:

0.00794

Gnomad SAS

AF:

0.0373

Gnomad FIN

AF:

0.00654

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0294

GnomAD2 exomes

AF:

0.0231

AC:

5769

AN:

250162

AF XY:

0.0248

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.00587

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0255

AC:

36543

AN:

1430266

Hom.:

553

Cov.:

AF XY:

0.0263

AC XY:

18769

AN XY:

713532

show subpopulations

African (AFR)

AF:

0.0140

AC:

460

AN:

32802

American (AMR)

AF:

0.0201

AC:

894

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

856

AN:

25850

East Asian (EAS)

AF:

0.00620

AC:

245

AN:

39502

South Asian (SAS)

AF:

0.0407

AC:

3482

AN:

85544

European-Finnish (FIN)

AF:

0.00619

AC:

330

AN:

53352

Middle Eastern (MID)

AF:

0.0430

AC:

245

AN:

5704

European-Non Finnish (NFE)

AF:

0.0262

AC:

28443

AN:

1083700

Other (OTH)

AF:

0.0268

AC:

1588

AN:

59310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1631

3263

4894

6526

8157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1112

2224

3336

4448

5560

<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:

0.0219

AC:

3318

AN:

151816

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1571

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.0153

AC:

634

AN:

41438

American (AMR)

AF:

0.0283

AC:

431

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.0298

AC:

103

AN:

3460

East Asian (EAS)

AF:

0.00796

AC:

AN:

5152

South Asian (SAS)

AF:

0.0383

AC:

184

AN:

4798

European-Finnish (FIN)

AF:

0.00654

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1758

AN:

67900

Other (OTH)

AF:

0.0290

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

160

320

479

639

799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0184

Hom.:

Bravo

AF:

0.0222

Asia WGS

AF:

0.0210

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.18

(source)

DANN

Benign

0.43

PhyloP100

-0.23

PromoterAI

-0.0092

Neutral

(source)

Mutation Taster

=100/0

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