Variant 5-141945390-C-CCTG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_016580.4(PCDH12):c.3543_3545dupCAG(p.Ser1181dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,551,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PCDH12
NM_016580.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Variant links:

Genes affected

PCDH12 (HGNC:8657): (protocadherin 12) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 6 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene localizes to the region on chromosome 5 where the protocadherin gene clusters reside. The exon organization of this transcript is similar to that of the gene cluster transcripts, notably the first large exon, but no significant sequence homology exists. The function of this cellular adhesion protein is undetermined but mouse protocadherin 12 does not bind catenins and appears to have no affect on cell migration or growth. [provided by RefSeq, Jul 2008]

PCDH12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000133 (187/1401904) while in subpopulation AMR AF= 0.000352 (15/42646). AF 95% confidence interval is 0.000216. There are 0 homozygotes in gnomad4_exome. There are 98 alleles in male gnomad4_exome subpopulation. Median coverage is 59. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH12	NM_016580.4 linkuse as main transcript	c.3543_3545dupCAG	p.Ser1181dup	disruptive_inframe_insertion	4/4	ENST00000231484.4	NP_057664.1	Q9NPG4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH12	ENST00000231484.4 linkuse as main transcript	c.3543_3545dupCAG	p.Ser1181dup	disruptive_inframe_insertion	4/4	1	NM_016580.4	ENSP00000231484.3		Q9NPG4

Frequencies

GnomAD3 genomes

AF:

0.000154

AC:

AN:

149116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000730

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00290

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000106

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

187

AN:

1401904

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

697160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.000352

Gnomad4 ASJ exome

AF:

0.00278

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000846

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000787

Gnomad4 OTH exome

AF:

0.000172

GnomAD4 genome

AF:

0.000154

AC:

AN:

149116

Hom.:

Cov.:

AF XY:

0.0000962

AC XY:

AN XY:

72794

show subpopulations

Gnomad4 AFR

AF:

0.0000730

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00290

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000106

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with PCDH12-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.3543_3545dup, results in the insertion of 1 amino acid(s) of the PCDH12 protein (p.Ser1181dup), but otherwise preserves the integrity of the 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