rs587784312

Positions:

• chr21-46411793-AGCAGCCCCTG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000359568.10(PCNT):​c.5727_5736del​(p.Leu1910GlyfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PCNT ENST00000359568.10 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.26

Genes affected

PCNT (HGNC:16068): (pericentrin) The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-46411793-AGCAGCCCCTG-A is Pathogenic according to our data. Variant chr21-46411793-AGCAGCCCCTG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.5727_5736del	p.Leu1910GlyfsTer29	frameshift_variant	28/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.5373_5382del	p.Leu1792GlyfsTer29	frameshift_variant	28/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.5727_5736del	p.Leu1910GlyfsTer29	frameshift_variant	28/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000909 AC: 2 AN: 219914 Hom.: 0 AF XY: 0.00000817 AC XY: 1 AN XY: 122428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447452 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 719742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000910

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 05, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 159623). This variant has not been reported in the literature in individuals affected with PCNT-related conditions. This variant is present in population databases (rs768128082, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Leu1910Glyfs*29) in the PCNT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCNT are known to be pathogenic (PMID: 18174396, 22821869). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

PCNT-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The PCNT c.5727_5736del10 variant is predicted to result in a frameshift and premature protein termination (p.Leu1910Glyfs*29). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0060% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PCNT are expected to be pathogenic. This variant is interpreted as pathogenic. -

Microcephalic osteodysplastic primordial dwarfism type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 05, 2013

- -

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: rs587784312; hg19: chr21-47831707;