Genetic Variant PCDH15:c.1917+25_1917+34dupGTGTGTGTGT (chr10-54132840-T-TACACACACAC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001384140.1(PCDH15):c.1917+25_1917+34dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCDH15
NM_001384140.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0900

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.1917+25_1917+34dupGTGTGTGTGT	intron	N/A	NP_149045.3
PCDH15	NM_001384140.1	MANE Select	c.1917+25_1917+34dupGTGTGTGTGT	intron	N/A	NP_001371069.1	Q96QU1-7
PCDH15	NM_001142763.2		c.1932+25_1932+34dupGTGTGTGTGT	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.1917+34_1917+35insGTGTGTGTGT	intron	N/A	ENSP00000322604.6	Q96QU1-1
PCDH15	ENST00000644397.2	MANE Select	c.1917+34_1917+35insGTGTGTGTGT	intron	N/A	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000395445.6	TSL:1	c.1938+34_1938+35insGTGTGTGTGT	intron	N/A	ENSP00000378832.2	Q96QU1-4

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000297

AC:

AN:

1345758

Hom.:

Cov.:

AF XY:

0.00000450

AC XY:

AN XY:

666796

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30616

American (AMR)

AF:

0.00

AC:

AN:

36908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23898

East Asian (EAS)

AF:

0.00

AC:

AN:

34394

South Asian (SAS)

AF:

0.0000257

AC:

AN:

77752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5428

European-Non Finnish (NFE)

AF:

9.69e-7

AC:

AN:

1032352

Other (OTH)

AF:

0.0000179

AC:

AN:

55878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0686974), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40880

American (AMR)

AF:

0.00

AC:

AN:

15090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.000196

AC:

AN:

5094

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67512

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.090

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-54132840-TACACACACACAC-TACACACACACACACACACACAC

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