rs181690344

chr21-46353115-C-T

Variant summary

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

The NM_006031.6(PCNT):c.1468C>T(p.Gln490Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000143 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PCNT NM_006031.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 3.61

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 21-46353115-C-T is Pathogenic according to our data. Variant chr21-46353115-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 159565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.1468C>T	p.Gln490Ter	stop_gained	10/47	ENST00000359568.10
PCNT	NM_001315529.2	c.1114C>T	p.Gln372Ter	stop_gained	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.1468C>T	p.Gln490Ter	stop_gained	10/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250836 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.0000109 AC: 16 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000623 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Colombian founder variant -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Nov 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2023

This sequence change creates a premature translational stop signal (p.Gln490*) 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). This variant is present in population databases (rs181690344, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with microcephalic osteodysplastic primordial dwarfism (PMID: 22821869, 24928221). ClinVar contains an entry for this variant (Variation ID: 159565). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.64
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs181690344; hg19: chr21-47773029;