21-46416552-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006031.6(PCNT):c.6634C>T(p.Arg2212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,612,910 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2212Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0049 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 38 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.488

Publications

11 publications found

Variant links:

COSMIC-nc: COSV107464416

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 Gene-Disease associations (from GenCC):

microcephalic osteodysplastic primordial dwarfism type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Moyamoya disease
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

PCNT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044667125).

BP6

Variant 21-46416552-C-T is Benign according to our data. Variant chr21-46416552-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0049 (746/152330) while in subpopulation NFE AF = 0.00491 (334/68028). AF 95% confidence interval is 0.00448. There are 6 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.6634C>T	p.Arg2212Trp	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6280C>T	p.Arg2094Trp	missense	Exon 30 of 47	NP_001302458.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.6634C>T	p.Arg2212Trp	missense	Exon 30 of 47	ENSP00000352572.5
PCNT	ENST00000480896.5	TSL:1	c.6280C>T	p.Arg2094Trp	missense	Exon 30 of 47	ENSP00000511989.1
PCNT	ENST00000695558.1		c.6667C>T	p.Arg2223Trp	missense	Exon 31 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes

AF:

0.00490

AC:

746

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0284

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00491

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00537

AC:

1344

AN:

250226

AF XY:

0.00554

show subpopulations

Gnomad AFR exome

AF:

0.000503

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00518

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.00541

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00510

AC:

7454

AN:

1460580

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

3649

AN XY:

726568

show subpopulations

African (AFR)

AF:

0.000749

AC:

AN:

33398

American (AMR)

AF:

0.00155

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

139

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86244

European-Finnish (FIN)

AF:

0.0251

AC:

1322

AN:

52760

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00491

AC:

5456

AN:

1111610

Other (OTH)

AF:

0.00466

AC:

281

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

458

916

1375

1833

2291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00490

AC:

746

AN:

152330

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

431

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41582

American (AMR)

AF:

0.00301

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0284

AC:

301

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00491

AC:

334

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00426

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00508

AC:

617

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Microcephalic osteodysplastic primordial dwarfism type II (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PhyloP100

-0.49

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Benign

0.061

Sift

Benign

0.036

Sift4G

Uncertain

0.035

Polyphen

1.0

Vest4

0.19

MVP

0.51

MPC

0.13

ClinPred

0.019

GERP RS

-2.7

Varity_R

0.042

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over