10-53866870-GAA-GA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_033056.4(PCDH15):c.3502-14delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,480,142 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 22)

Exomes 𝑓: 0.0011 ( 11 hom. )

Consequence

PCDH15
NM_033056.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.936

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, 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 -16 ACMG points.

BP6

Variant 10-53866870-GA-G is Benign according to our data. Variant chr10-53866870-GA-G is described in ClinVar as Benign. ClinVar VariationId is 179543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (415/150054) while in subpopulation AFR AF = 0.00802 (329/41008). AF 95% confidence interval is 0.00731. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.3502-14delT		intron_variant	Intron 26 of 32	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.3502-14delT		intron_variant	Intron 26 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.3502-14delT		intron_variant	Intron 26 of 32	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.3502-14delT		intron_variant	Intron 26 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

414

AN:

149950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00802

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000996

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00755

Gnomad FIN

AF:

0.000399

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000356

Gnomad OTH

AF:

0.00146

GnomAD2 exomes

AF:

0.00189

AC:

439

AN:

232130

AF XY:

0.00204

show subpopulations

Gnomad AFR exome

AF:

0.00869

Gnomad AMR exome

AF:

0.000541

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000629

Gnomad FIN exome

AF:

0.000298

Gnomad NFE exome

AF:

0.000462

Gnomad OTH exome

AF:

0.000538

GnomAD4 exome

AF:

0.00106

AC:

1404

AN:

1330088

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

815

AN XY:

668006

show subpopulations

African (AFR)

AF:

0.00826

AC:

243

AN:

29420

American (AMR)

AF:

0.000711

AC:

AN:

42170

Ashkenazi Jewish (ASJ)

AF:

0.0000401

AC:

AN:

24926

East Asian (EAS)

AF:

0.0000292

AC:

AN:

34290

South Asian (SAS)

AF:

0.00783

AC:

637

AN:

81340

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

52284

Middle Eastern (MID)

AF:

0.00184

AC:

AN:

5430

European-Non Finnish (NFE)

AF:

0.000410

AC:

412

AN:

1004750

Other (OTH)

AF:

0.00115

AC:

AN:

55478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00277

AC:

415

AN:

150054

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

203

AN XY:

73118

show subpopulations

African (AFR)

AF:

0.00802

AC:

329

AN:

41008

American (AMR)

AF:

0.000995

AC:

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5090

South Asian (SAS)

AF:

0.00799

AC:

AN:

4758

European-Finnish (FIN)

AF:

0.000399

AC:

AN:

10024

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000327

AC:

AN:

67366

Other (OTH)

AF:

0.00144

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

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:

0.000724

Hom.:

212

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 25, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PCDH15 c.3502-14delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0019 in 232130 control chromosomes, predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3502-14delT in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Apr 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

3502-14delT in intron 26 of PCDH15: This variant is not expected to have clinic al significance because it is not predicted to alter splicing and has been ident ified in 0.6% (46/8254) European American chromosomes and in 1.2% (53/4264) Afri can American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu; dbSNP rs5785023). -

not provided

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.94

Mutation Taster

=100/0

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

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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