5-141945401-T-TGCTGCTGCTGCTGCTGCC

Variant names:

• chr5-141945401-T-TGCTGCTGCTGCTGCTGCC
• rs532090538
• NM_016580.4:c.3534_3535insGGCAGCAGCAGCAGCAGC

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.3534_3535insGGCAGCAGCAGCAGCAGC​(p.Ser1178_Ser1179insGlySerSerSerSerSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 152,260 control chromosomes in the GnomAD database, including 44 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (44 hom., cov: 33)
  • Exomes 𝑓: 0.027 (265 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDH12 NM_016580.4 conservative_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.82
• Publications: 1 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 5-141945401-T-TGCTGCTGCTGCTGCTGCC is Benign according to our data. Variant chr5-141945401-T-TGCTGCTGCTGCTGCTGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 773463.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0197 (2996/152260) while in subpopulation NFE AF = 0.0297 (2018/67998). AF 95% confidence interval is 0.0286. There are 44 homozygotes in GnomAd4. There are 1441 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 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.3534_3535insGGCAGCAGCAGCAGCAGC	p.Ser1178_Ser1179insGlySerSerSerSerSer	conservative_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_3535insGGCAGCAGCAGCAGCAGC	p.Ser1178_Ser1179insGlySerSerSerSerSer	conservative_inframe_insertion	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1391_*2-1390insTGCTGCTGCCGCTGCTGC		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2995 AN: 152142 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0204 AC: 5046 AN: 247386 AF XY: 0.0209

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00697

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0166

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0265 AC: 38724 AN: 1458770 Hom.: 265 Cov.: 67 AF XY: 0.0262 AC XY: 18997 AN XY: 725616

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

African (AFR) AF: 0.00368 AC: 123 AN: 33444

American (AMR) AF: 0.00573 AC: 256 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00695 AC: 181 AN: 26046

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0169 AC: 1456 AN: 86172

European-Finnish (FIN) AF: 0.0421 AC: 2221 AN: 52798

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5762

European-Non Finnish (NFE) AF: 0.0299 AC: 33142 AN: 1109958

Other (OTH) AF: 0.0214 AC: 1290 AN: 60236

⚠️ 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: 0.0197 AC: 2996 AN: 152260 Hom.: 44 Cov.: 33 AF XY: 0.0194 AC XY: 1441 AN XY: 74450

African (AFR) AF: 0.00512 AC: 213 AN: 41574

American (AMR) AF: 0.00941 AC: 144 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0154 AC: 74 AN: 4820

European-Finnish (FIN) AF: 0.0468 AC: 497 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2018 AN: 67998

Other (OTH) AF: 0.0124 AC: 26 AN: 2104

Alfa AF: 0.0128 Hom.: 5

ClinVar

ClinVar submissions

Significance: Likely 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		2.8
Mutation Taster		=88/12	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs532090538; hg19: chr5-141324966; COSMIC: COSV51521762; COSMIC: COSV51521762;