5-141945390-C-CCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_016580.4(PCDH12):c.3545_3546insCAGCAGCAG(p.Ser1179_Ser1181dup) variant causes a 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 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71

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]

ACMG classification

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/exons	MANE	UniProt
PCDH12	NM_016580.4	c.3545_3546insCAGCAGCAG	p.Ser1179_Ser1181dup	inframe_insertion	4/4	ENST00000231484.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH12	ENST00000231484.4	c.3545_3546insCAGCAGCAG	p.Ser1179_Ser1181dup	inframe_insertion	4/4	1	NM_016580.4	P1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 61041 AN: 149040 Hom.: 13098 Cov.: 0

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.: 59 AF XY: 0.390 AC XY: 271522 AN XY: 696896

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.: 0 AF XY: 0.418 AC XY: 30434 AN XY: 72876

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

PCDH12-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5871792; hg19: chr5-141324955;