5-141945401-T-TGCTGCTGCTGCTGCTGCC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_016580.4(PCDH12):c.3534_3535insGGCAGCAGCAGCAGCAGC(p.Ser1178_Ser1179insGlySerSerSerSerSer) variant causes a 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. 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 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.82

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH12	NM_016580.4	c.3534_3535insGGCAGCAGCAGCAGCAGC	p.Ser1178_Ser1179insGlySerSerSerSerSer	inframe_insertion	4/4	ENST00000231484.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH12	ENST00000231484.4	c.3534_3535insGGCAGCAGCAGCAGCAGC	p.Ser1178_Ser1179insGlySerSerSerSerSer	inframe_insertion	4/4	1	NM_016580.4	P1

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

GnomAD3 exomes AF: 0.0204 AC: 5046 AN: 247386 Hom.: 39 AF XY: 0.0209 AC XY: 2801 AN XY: 134210

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 SAS exome AF: 0.0165

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

Gnomad4 AFR exome AF: 0.00368

Gnomad4 AMR exome AF: 0.00573

Gnomad4 ASJ exome AF: 0.00695

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0421

Gnomad4 NFE exome AF: 0.0299

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0197 AC: 2996 AN: 152260 Hom.: 44 Cov.: 33 AF XY: 0.0194 AC XY: 1441 AN XY: 74450

Gnomad4 AFR AF: 0.00512

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.0128 Hom.: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs532090538; hg19: chr5-141324966;