rs757577162

chr21-46412065-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006031.6(PCNT):c.5992C>T(p.Gln1998Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000467 in 1,606,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

PCNT
NM_006031.6 stop_gained, splice_region

Scores

Splicing: ADA: 0.5190

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -1.16

Variant links:

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]

PCNT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 21-46412065-C-T is Pathogenic according to our data. Variant chr21-46412065-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 436268.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 linkuse as main transcript	c.5992C>T	p.Gln1998Ter	stop_gained, splice_region_variant	28/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.5638C>T	p.Gln1880Ter	stop_gained, splice_region_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.5992C>T	p.Gln1998Ter	stop_gained, splice_region_variant	28/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

234872

Hom.:

AF XY:

0.00

AC XY:

AN XY:

128838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000571

Gnomad NFE exome

AF:

0.00000963

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000488

AC:

AN:

1454044

Hom.:

Cov.:

AF XY:

0.0000511

AC XY:

AN XY:

723622

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000634

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000830

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PCNT: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Gln1998*) 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 (rs757577162, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with microcephalic osteodysplastic primordial dwarfism type II (PMID: 18174396). ClinVar contains an entry for this variant (Variation ID: 436268). For these reasons, this variant has been classified as Pathogenic. -

PCNT-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

The PCNT c.5992C>T variant is predicted to result in premature protein termination (p.Gln1998*). This variant, with a second PCNT variant, has been reported in individuals with microcephalic osteodysplastic primordial dwarfism type 2 (Table S2, Rauch et al. 2008. PubMed ID: 18174396; Table S1, Bober et al. 2012. PubMed ID: 22821869). This variant is reported in 0.0057% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense 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

Aug 30, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Uncertain

0.030

Cadd

Pathogenic

Dann

Benign

0.97

Eigen

Benign

-0.67

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.018

MutationTaster

Benign

1.0

Vest4

0.54

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.52

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over