21-46436140-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006031.6(PCNT):c.8988C>T(p.Ala2996Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 1,607,646 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2996A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 87 hom., cov: 33)

Exomes 𝑓: 0.036 ( 1088 hom. )

Consequence

PCNT
NM_006031.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.98

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 21-46436140-C-T is Benign according to our data. Variant chr21-46436140-C-T is described in ClinVar as [Benign]. Clinvar id is 95344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46436140-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.98 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0265 (4038/152342) while in subpopulation NFE AF= 0.04 (2720/68030). AF 95% confidence interval is 0.0387. There are 87 homozygotes in gnomad4. There are 1877 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 87 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6 link	c.8988C>T	p.Ala2996Ala	synonymous_variant	Exon 39 of 47	ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 link	c.8397C>T	p.Ala2799Ala	synonymous_variant	Exon 39 of 47		NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 link	c.8988C>T	p.Ala2996Ala	synonymous_variant	Exon 39 of 47	1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4040

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00697

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00910

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0400

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0267

AC:

6271

AN:

235178

Hom.:

AF XY:

0.0266

AC XY:

3440

AN XY:

129312

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00927

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0404

Gnomad OTH exome

AF:

0.0305

GnomAD4 exome

AF:

0.0358

AC:

52152

AN:

1455304

Hom.:

1088

Cov.:

AF XY:

0.0352

AC XY:

25484

AN XY:

724322

show subpopulations

Gnomad4 AFR exome

AF:

0.00604

Gnomad4 AMR exome

AF:

0.0174

Gnomad4 ASJ exome

AF:

0.0473

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00997

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0412

Gnomad4 OTH exome

AF:

0.0326

GnomAD4 genome

AF:

0.0265

AC:

4038

AN:

152342

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1877

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00695

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0513

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00890

Gnomad4 FIN

AF:

0.0230

Gnomad4 NFE

AF:

0.0400

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.0281

Hom.:

Bravo

AF:

0.0259

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephalic osteodysplastic primordial dwarfism type II

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.13

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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