Variant rs143978284 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4_SupportingPP3BP6_Very_StrongBA1

The NM_001384140.1(PCDH15):c.4730_4731insAAC(p.Thr1577_Gly1577insThr) variant causes a inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,613,496 control chromosomes in the GnomAD database, including 226 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 115 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 111 hom. )

Consequence

PCDH15
NM_001384140.1 inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.60

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001384140.1. Strenght limited to Supporting due to length of the change: 1aa.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 10-53807071-A-AGTT is Benign according to our data. Variant chr10-53807071-A-AGTT is described in ClinVar as [Benign]. Clinvar id is 227002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_001384140.1 linkuse as main transcript	c.4730_4731insAAC	p.Thr1577_Gly1577insThr	inframe_insertion	38/38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4730_4731insAAC	p.Thr1577_Gly1577insThr	inframe_insertion	38/38		NM_001384140.1	ENSP00000495195

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3196

AN:

152122

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0717

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00976

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.00551

AC:

1365

AN:

247692

Hom.:

AF XY:

0.00412

AC XY:

555

AN XY:

134640

show subpopulations

Gnomad AFR exome

AF:

0.0721

Gnomad AMR exome

AF:

0.00476

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000446

Gnomad OTH exome

AF:

0.00416

GnomAD4 exome

AF:

0.00253

AC:

3700

AN:

1461256

Hom.:

111

Cov.:

AF XY:

0.00218

AC XY:

1585

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.0759

Gnomad4 AMR exome

AF:

0.00520

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000435

Gnomad4 OTH exome

AF:

0.00580

GnomAD4 genome

AF:

0.0211

AC:

3206

AN:

152240

Hom.:

115

Cov.:

AF XY:

0.0203

AC XY:

1510

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0718

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.00912

Hom.:

Bravo

AF:

0.0243

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000656

EpiControl

AF:

0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

p.Thr1519dup in exon 36C of PCDH15: This variant is not expected to have clinica l significance because it has been identified in 7.3% (707/9652) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs143978284). This variant is an insertion of 1 amino acid at position 1519 and is not predicted to alter the protein reading-frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over