NM_016580.4:c.3540_3545dupCAGCAG

Variant names:

• chr5-141945390-C-CCTGCTG
• rs5871792
• NM_016580.4:c.3540_3545dupCAGCAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_016580.4(PCDH12):​c.3540_3545dupCAGCAG​(p.Ser1180_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 0.00228 in 1,447,016 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: PCDH12 NM_016580.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 5-141945390-C-CCTGCTG is Benign according to our data. Variant chr5-141945390-C-CCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 769662.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00762 (1137/149138) while in subpopulation AFR AF = 0.0264 (1090/41230). AF 95% confidence interval is 0.0251. There are 15 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.3540_3545dupCAGCAG	p.Ser1180_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.3540_3545dupCAGCAG	p.Ser1180_Ser1181dup	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1396_*2-1391dupTGCTGC		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes AF: 0.00762 AC: 1135 AN: 149024 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00292

GnomAD4 exome AF: 0.00166 AC: 2158 AN: 1297878 Hom.: 8 Cov.: 59 AF XY: 0.00164 AC XY: 1055 AN XY: 643070

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0276 AC: 884 AN: 31978

American (AMR) AF: 0.00668 AC: 237 AN: 35478

Ashkenazi Jewish (ASJ) AF: 0.00150 AC: 35 AN: 23270

East Asian (EAS) AF: 0.00294 AC: 76 AN: 25810

South Asian (SAS) AF: 0.00248 AC: 173 AN: 69850

European-Finnish (FIN) AF: 0.000918 AC: 43 AN: 46840

Middle Eastern (MID) AF: 0.00263 AC: 14 AN: 5328

European-Non Finnish (NFE) AF: 0.000562 AC: 565 AN: 1005594

Other (OTH) AF: 0.00244 AC: 131 AN: 53730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00762 AC: 1137 AN: 149138 Hom.: 15 Cov.: 0 AF XY: 0.00704 AC XY: 513 AN XY: 72862

African (AFR) AF: 0.0264 AC: 1090 AN: 41230

American (AMR) AF: 0.00186 AC: 28 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.000631 AC: 3 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000151 AC: 10 AN: 66162

Other (OTH) AF: 0.00288 AC: 6 AN: 2080

Alfa AF: 0.0222 Hom.: 816

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;