NM_016580.4:c.3537_3545dupCAGCAGCAG

Variant names:

• chr5-141945390-C-CCTGCTGCTG
• rs5871792
• NM_016580.4:c.3537_3545dupCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -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 VariationId 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.

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.3537_3545dupCAGCAGCAG	p.Ser1179_Ser1181dup	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.3537_3545dupCAGCAGCAG	p.Ser1179_Ser1181dup	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1399_*2-1391dupTGCTGCTGC		intron	N/A	ENSP00000565988.1

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

African (AFR) AF: 0.270 AC: 8917 AN: 33028

American (AMR) AF: 0.537 AC: 22921 AN: 42644

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 9828 AN: 25170

East Asian (EAS) AF: 0.653 AC: 24416 AN: 37414

South Asian (SAS) AF: 0.489 AC: 40485 AN: 82718

European-Finnish (FIN) AF: 0.364 AC: 18196 AN: 49992

Middle Eastern (MID) AF: 0.427 AC: 2389 AN: 5600

European-Non Finnish (NFE) AF: 0.369 AC: 393264 AN: 1066622

Other (OTH) AF: 0.391 AC: 22755 AN: 58222

GnomAD4 genome AF: 0.409 AC: 61073 AN: 149154 Hom.: 13105 Cov.: 0 AF XY: 0.418 AC XY: 30434 AN XY: 72876

African (AFR) AF: 0.290 AC: 11958 AN: 41212

American (AMR) AF: 0.532 AC: 8021 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1480 AN: 3454

East Asian (EAS) AF: 0.807 AC: 4085 AN: 5060

South Asian (SAS) AF: 0.582 AC: 2766 AN: 4750

European-Finnish (FIN) AF: 0.415 AC: 4213 AN: 10148

Middle Eastern (MID) AF: 0.401 AC: 113 AN: 282

European-Non Finnish (NFE) AF: 0.412 AC: 27232 AN: 66172

Other (OTH) AF: 0.451 AC: 940 AN: 2082

Alfa AF: 0.300 Hom.: 816

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Diencephalic-mesencephalic junction dysplasia syndrome 1 (1)
-	-	1	PCDH12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=84/16	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; COSMIC: COSV51518868; COSMIC: COSV51518868;