Genetic Variant PCDH12:p.Ser1179_Ser1181dup (chr5-141945390-C-CCTGCTGCTG) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_016580.4(PCDH12):c.3537_3545dupCAGCAGCAG(p.Ser1179_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 0.39 in 1,550,564 control chromosomes in the GnomAD database, including 86,754 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13105 hom., cov: 0)

Exomes 𝑓: 0.39 ( 73649 hom. )

Consequence

PCDH12
NM_016580.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 5-141945390-C-CCTGCTGCTG is Benign according to our data. Variant chr5-141945390-C-CCTGCTGCTG is described in ClinVar as [Benign]. Clinvar id is 768040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH12	NM_016580.4 link	c.3537_3545dupCAGCAGCAG	p.Ser1179_Ser1181dup	disruptive_inframe_insertion	Exon 4 of 4	ENST00000231484.4	NP_057664.1	Q9NPG4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH12	ENST00000231484.4 link	c.3537_3545dupCAGCAGCAG	p.Ser1179_Ser1181dup	disruptive_inframe_insertion	Exon 4 of 4	1	NM_016580.4	ENSP00000231484.3		Q9NPG4

Frequencies

GnomAD3 genomes

AF:

0.410

AC:

61041

AN:

149040

Hom.:

13098

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.428

Gnomad EAS

AF:

0.808

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.412

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.450

GnomAD4 exome

AF:

0.388

AC:

543171

AN:

1401410

Hom.:

73649

Cov.:

AF XY:

0.390

AC XY:

271522

AN XY:

696896

show subpopulations

Gnomad4 AFR exome

AF:

0.270

Gnomad4 AMR exome

AF:

0.537

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.653

Gnomad4 SAS exome

AF:

0.489

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.369

Gnomad4 OTH exome

AF:

0.391

GnomAD4 genome

AF:

0.409

AC:

61073

AN:

149154

Hom.:

13105

Cov.:

AF XY:

0.418

AC XY:

30434

AN XY:

72876

show subpopulations

Gnomad4 AFR

AF:

0.290

Gnomad4 AMR

AF:

0.532

Gnomad4 ASJ

AF:

0.428

Gnomad4 EAS

AF:

0.807

Gnomad4 SAS

AF:

0.582

Gnomad4 FIN

AF:

0.415

Gnomad4 NFE

AF:

0.412

Gnomad4 OTH

AF:

0.451

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCDH12-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Diencephalic-mesencephalic junction dysplasia syndrome 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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