5-141945390-C-CCTG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_016580.4(PCDH12):c.3545_3546insCAG(p.Ser1181dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 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 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 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	UniProt
PCDH12	NM_016580.4	c.3545_3546insCAG	p.Ser1181dup	inframe_insertion	4/4	ENST00000231484.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH12	ENST00000231484.4	c.3545_3546insCAG	p.Ser1181dup	inframe_insertion	4/4	1	NM_016580.4	P1

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 23 AN: 149116 Hom.: 0 Cov.: 0

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.: 0 Cov.: 59 AF XY: 0.000141 AC XY: 98 AN XY: 697160

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: 23 AN: 149116 Hom.: 0 Cov.: 0 AF XY: 0.0000962 AC XY: 7 AN XY: 72794

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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

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;