21-46391269-G-A

Position:

chr21-46391269-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000359568.10(PCNT):c.4109G>A(p.Arg1370Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,596,248 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1370W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00056 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

PCNT
ENST00000359568.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -1.98

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004022807).

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.4109G>A	p.Arg1370Gln	missense_variant	21/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2 linkuse as main transcript	c.3755G>A	p.Arg1252Gln	missense_variant	21/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.4109G>A	p.Arg1370Gln	missense_variant	21/47	1	NM_006031.6	ENSP00000352572	P2	O95613-1
PCNT	ENST00000480896.5 linkuse as main transcript	c.3755G>A	p.Arg1252Gln	missense_variant	21/47	1		ENSP00000511989	A2	O95613-2
PCNT	ENST00000695558.1 linkuse as main transcript	c.4109G>A	p.Arg1370Gln	missense_variant	21/48			ENSP00000512015	A2
PCNT	ENST00000703224.1 linkuse as main transcript	c.*3352G>A		3_prime_UTR_variant, NMD_transcript_variant	23/49			ENSP00000515242

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000328

AC:

AN:

213462

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

115334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000374

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.000444

Gnomad OTH exome

AF:

0.000925

GnomAD4 exome

AF:

0.000281

AC:

406

AN:

1443930

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

184

AN XY:

716324

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.000961

Gnomad4 NFE exome

AF:

0.000304

Gnomad4 OTH exome

AF:

0.000301

GnomAD4 genome

AF:

0.000565

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000373

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1370 of the PCNT protein (p.Arg1370Gln). This variant is present in population databases (rs145055342, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PCNT-related conditions. ClinVar contains an entry for this variant (Variation ID: 195605). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2015	- -

Microcephalic osteodysplastic primordial dwarfism type II

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2020	- -

PCNT-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The PCNT c.4109G>A variant is predicted to result in the amino acid substitution p.Arg1370Gln. To our knowledge, this variant has not been reported in individuals with PCNT-associated disorders in the literature. This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD, which may be too common to be an undocumented primary cause of disease. Although we suspect this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0060

DANN

Benign

0.43

DEOGEN2

Benign

0.014

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.32

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

1.1

REVEL

Benign

0.028

Sift

Benign

0.84

Sift4G

Benign

0.67

Polyphen

0.024

Vest4

0.079

MVP

0.37

MPC

0.093

ClinPred

0.011

GERP RS

-10

Varity_R

0.013

gMVP

0.013

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