5-141945390-CCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr5-141945390-C-CCTGCTGCTGCTGCTGCTGCTG
• rs5871792
• NM_016580.4:c.3545_3546insCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_016580.4(PCDH12):​c.3545_3546insCAGCAGCAGCAGCAGCAGCAG​(p.Ser1181_Arg1182insSerSerSerSerSerSerSer) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,551,174 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000094 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: PCDH12 NM_016580.4 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 14 publications found

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]

DELE1 (HGNC:28969): (DAP3 binding cell death enhancer 1) Enables protein kinase binding activity and protein serine/threonine kinase activator activity. Involved in HRI-mediated signaling; extrinsic apoptotic signaling pathway via death domain receptors; and regulation of cysteine-type endopeptidase activity involved in apoptotic process. Located in cytosol and mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000939 (14/149116) while in subpopulation AMR AF = 0.000796 (12/15080). AF 95% confidence interval is 0.000459. There are 1 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016580.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	NM_016580.4	MANE Select	c.3545_3546insCAGCAGCAGCAGCAGCAGCAG	p.Ser1181_Arg1182insSerSerSerSerSerSerSer	disruptive_inframe_insertion	Exon 4 of 4	NP_057664.1	Q9NPG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	ENST00000231484.4	TSL:1 MANE Select	c.3545_3546insCAGCAGCAGCAGCAGCAGCAG	p.Ser1181_Arg1182insSerSerSerSerSerSerSer	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1391_*2-1390insTGCTGCTGCTGCTGCTGCTGC		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes AF: 0.0000939 AC: 14 AN: 149116 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000796

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000970

GnomAD4 exome AF: 0.00000499 AC: 7 AN: 1402058 Hom.: 0 Cov.: 59 AF XY: 0.00000861 AC XY: 6 AN XY: 697228

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 42656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 37418

South Asian (SAS) AF: 0.00 AC: 0 AN: 82742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1067034

Other (OTH) AF: 0.0000859 AC: 5 AN: 58240

GnomAD4 genome AF: 0.0000939 AC: 14 AN: 149116 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72794

African (AFR) AF: 0.00 AC: 0 AN: 41124

American (AMR) AF: 0.000796 AC: 12 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66198

Other (OTH) AF: 0.000970 AC: 2 AN: 2062

Alfa AF: 0.0000571 Hom.: 816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs5871792; hg19: chr5-141324955;