5-141945390-CCTGCTG-CCTGCTGCTGCTGCTGCTG

Variant names:

• chr5-141945390-C-CCTGCTGCTGCTG
• rs5871792
• NM_016580.4:c.3534_3545dupCAGCAGCAGCAG

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.3534_3545dupCAGCAGCAGCAG​(p.Ser1178_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 0.00436 in 1,551,240 control chromosomes in the GnomAD database, including 182 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (124 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (58 hom.)
• Consequence: PCDH12 NM_016580.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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-CCTGCTGCTGCTG is Benign according to our data. Variant chr5-141945390-C-CCTGCTGCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 1164145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0728 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.3534_3545dupCAGCAGCAGCAG	p.Ser1178_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.3534_3545dupCAGCAGCAGCAG	p.Ser1178_Ser1181dup	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1402_*2-1391dupTGCTGCTGCTGC		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3252 AN: 149104 Hom.: 124 Cov.: 0

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.00316

Gnomad FIN AF: 0.000295

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000302

Gnomad OTH AF: 0.0175

GnomAD4 exome AF: 0.00249 AC: 3489 AN: 1402022 Hom.: 58 Cov.: 59 AF XY: 0.00227 AC XY: 1586 AN XY: 697204

African (AFR) AF: 0.0736 AC: 2437 AN: 33094

American (AMR) AF: 0.00382 AC: 163 AN: 42656

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25170

East Asian (EAS) AF: 0.000775 AC: 29 AN: 37416

South Asian (SAS) AF: 0.00228 AC: 189 AN: 82742

European-Finnish (FIN) AF: 0.000399 AC: 20 AN: 50096

Middle Eastern (MID) AF: 0.00411 AC: 23 AN: 5602

European-Non Finnish (NFE) AF: 0.000327 AC: 349 AN: 1067008

Other (OTH) AF: 0.00477 AC: 278 AN: 58238

GnomAD4 genome AF: 0.0219 AC: 3268 AN: 149218 Hom.: 124 Cov.: 0 AF XY: 0.0216 AC XY: 1572 AN XY: 72914

African (AFR) AF: 0.0750 AC: 3093 AN: 41238

American (AMR) AF: 0.00623 AC: 94 AN: 15094

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

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5060

South Asian (SAS) AF: 0.00316 AC: 15 AN: 4752

European-Finnish (FIN) AF: 0.000295 AC: 3 AN: 10158

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 282

European-Non Finnish (NFE) AF: 0.000302 AC: 20 AN: 66188

Other (OTH) AF: 0.0173 AC: 36 AN: 2084

Alfa AF: 0.00114 Hom.: 816

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

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;