5-141945390-CCTG-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP6_Very_Strong BS1

The NM_016580.4(PCDH12):c.3543_3545del(p.Ser1181del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000834 in 1,546,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: PCDH12 NM_016580.4 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-141945390-CCTG-C is Benign according to our data. Variant chr5-141945390-CCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 1633528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000141 (21/149226) while in subpopulation EAS AF= 0.00198 (10/5060). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH12	NM_016580.4	c.3543_3545del	p.Ser1181del	inframe_deletion	4/4	ENST00000231484.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH12	ENST00000231484.4	c.3543_3545del	p.Ser1181del	inframe_deletion	4/4	1	NM_016580.4	P1

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 21 AN: 149112 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000773 AC: 108 AN: 1396890 Hom.: 0 AF XY: 0.0000950 AC XY: 66 AN XY: 694660

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.000279

Gnomad4 EAS exome AF: 0.000535

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.0000602

Gnomad4 NFE exome AF: 0.0000517

Gnomad4 OTH exome AF: 0.000241

GnomAD4 genome AF: 0.000141 AC: 21 AN: 149226 Hom.: 0 Cov.: 0 AF XY: 0.000178 AC XY: 13 AN XY: 72918

Gnomad4 AFR AF: 0.000267

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00198

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00285 Hom.: 816

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PCDH12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 08, 2020

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs5871792; hg19: chr5-141324955;