21-46416534-A-G

Position:

chr21-46416534-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006031.6(PCNT):c.6616A>G(p.Thr2206Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,728 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 22 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 16 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.42

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027277768).

BP6

Variant 21-46416534-A-G is Benign according to our data. Variant chr21-46416534-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416534-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00781 (1189/152290) while in subpopulation AFR AF= 0.027 (1123/41554). AF 95% confidence interval is 0.0257. There are 22 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.6616A>G	p.Thr2206Ala	missense_variant	30/47	ENST00000359568.10
PCNT	NM_001315529.2 linkuse as main transcript	c.6262A>G	p.Thr2088Ala	missense_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.6616A>G	p.Thr2206Ala	missense_variant	30/47	1	NM_006031.6	P2	O95613-1

Frequencies

GnomAD3 genomes

AF:

0.00771

AC:

1173

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

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:

0.0000882

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00208

AC:

521

AN:

250582

Hom.:

AF XY:

0.00147

AC XY:

199

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.0293

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.000771

AC:

1127

AN:

1461438

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.0271

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00781

AC:

1189

AN:

152290

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

539

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0270

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00389

Hom.:

Bravo

AF:

0.00893

ESP6500AA

AF:

0.0270

AC:

119

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00254

AC:

308

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0050

DANN

Benign

0.25

DEOGEN2

Benign

0.020

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.72

MutationTaster

Benign

1.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.090

REVEL

Benign

0.044

Sift

Benign

0.79

Sift4G

Benign

0.97

Polyphen

0.0

Vest4

0.026

MVP

0.23

MPC

0.079

ClinPred

0.0030

GERP RS

-9.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.14

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