dbSNP rs2660169: PCDH15:c.2751+43C>G (chr10-54020149-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384140.1(PCDH15):c.2751+43C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 1,546,326 control chromosomes in the GnomAD database, including 11,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 4755 hom., cov: 32)

Exomes 𝑓: 0.057 ( 7028 hom. )

Consequence

PCDH15
NM_001384140.1 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0520

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 10-54020149-G-C is Benign according to our data. Variant chr10-54020149-G-C is described in ClinVar as [Benign]. Clinvar id is 262148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54020149-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.2751+43C>G		intron_variant	Intron 20 of 32	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 link	c.2751+43C>G		intron_variant	Intron 20 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.2751+43C>G		intron_variant	Intron 20 of 32	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 link	c.2751+43C>G		intron_variant	Intron 20 of 37		NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25218

AN:

151844

Hom.:

4731

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0862

Gnomad ASJ

AF:

0.0545

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.0276

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0308

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.0941

AC:

23292

AN:

247406

Hom.:

2945

AF XY:

0.0900

AC XY:

12048

AN XY:

133830

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.0476

Gnomad ASJ exome

AF:

0.0536

Gnomad EAS exome

AF:

0.254

Gnomad SAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0688

GnomAD4 exome

AF:

0.0568

AC:

79222

AN:

1394364

Hom.:

7028

Cov.:

AF XY:

0.0583

AC XY:

40711

AN XY:

697856

show subpopulations

Gnomad4 AFR exome

AF:

0.473

Gnomad4 AMR exome

AF:

0.0506

Gnomad4 ASJ exome

AF:

0.0540

Gnomad4 EAS exome

AF:

0.255

Gnomad4 SAS exome

AF:

0.150

Gnomad4 FIN exome

AF:

0.0290

Gnomad4 NFE exome

AF:

0.0292

Gnomad4 OTH exome

AF:

0.0847

GnomAD4 genome

AF:

0.166

AC:

25291

AN:

151962

Hom.:

4755

Cov.:

AF XY:

0.165

AC XY:

12263

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.457

Gnomad4 AMR

AF:

0.0861

Gnomad4 ASJ

AF:

0.0545

Gnomad4 EAS

AF:

0.262

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.0276

Gnomad4 NFE

AF:

0.0308

Gnomad4 OTH

AF:

0.138

Alfa

AF:

0.0409

Hom.:

113

Bravo

AF:

0.183

Asia WGS

AF:

0.240

AC:

831

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.7

DANN

Benign

0.46

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

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