rs770322907

Variant names:

Variant summary

Our verdict is The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PVS1_StrongPM2

The NM_001384140.1(PCDH15):c.5105_5108dupTTGA (p.Ser1704fs) variant causes a frameshift, stop gained change. This is a loss-of-function variant that does not trigger NMD. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.0000682 (AC=110) in the gnomAD database across 1,613,728 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000061. Variant has been reported in ClinVar as Uncertain Significance (★★).

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

PCDH15
NM_001384140.1 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.96

Publications

0 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Natera
Usher syndrome type 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
Usher syndrome type 1D
Inheritance: Unknown Classification: LIMITED Submitted by: Natera

PCDH15 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001384140.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 points.

PVS1

Non-NMD frameshift: ≥4 pathogenic in truncated region — strong (PVS1 downgraded to PS); Frameshift (exon 38 of 38) at amino acid 1703 of 1740; NMD not predicted. 4 pathogenic variants in the affected exon support its functional importance. A new stop codon is introduced in the shifted frame, truncating the protein to ~1703 amino acids (37 amino acids lost).

PM2

Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000061 — very rare for AR gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001384140.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCDH15	NM_001384140.1	MANE Select	c.5105_5108dupTTGA	p.Ser1704fs	frameshift stop_gained	Exon 38 of 38	NP_001371069.1	Q96QU1-7
PCDH15	NM_001354429.2		c.5039_5042dupTTGA	p.Ser1682fs	frameshift stop_gained	Exon 37 of 37	NP_001341358.1
PCDH15	NM_001142771.2		c.4931_4934dupTTGA	p.Ser1646fs	frameshift stop_gained	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.5105_5108dupTTGA	p.Ser1704fs	frameshift stop_gained	Exon 38 of 38	ENSP00000495195.1	Q96QU1-7
PCDH15	ENST00000616114.4	TSL:1	c.4910_4913dupTTGA	p.Ser1639fs	frameshift stop_gained	Exon 34 of 34	ENSP00000483745.1	Q96QU1-6
PCDH15	ENST00000621708.4	TSL:5	c.4931_4934dupTTGA	p.Ser1646fs	frameshift stop_gained	Exon 36 of 36	ENSP00000484454.1	A0A087X1T6

Frequencies

GnomAD3 genomes

AF:

0.0000763

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000381

Gnomad SAS

AF:

0.000214

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000916

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000763

AC:

AN:

248696

AF XY:

0.000107

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000504

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000610

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.0000610

AC XY:

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000610

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000107

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000610

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000763

AC:

AN:

1111792

Other (OTH)

AF:

0.0000458

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000763

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000916

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000458

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000381

AC:

AN:

5190

South Asian (SAS)

AF:

0.000214

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000916

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.0000458

Hom.:

Bravo

AF:

0.0000916

Local populations

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000335

AC:

AN:

8960

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=17/183

disease causing

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over