21-46411844-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.5771C>T(p.Ala1924Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00693 in 1,558,970 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1924A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0070 ( 45 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.32

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

microcephalic osteodysplastic primordial dwarfism type II
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
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=0.0041799545).

BP6

Variant 21-46411844-C-T is Benign according to our data. Variant chr21-46411844-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95339.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 = 0.00597 (909/152346) while in subpopulation NFE AF = 0.00894 (608/68032). AF 95% confidence interval is 0.00835. There are 3 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.5771C>T	p.Ala1924Val	missense	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5417C>T	p.Ala1806Val	missense	Exon 28 of 47	NP_001302458.1	O95613-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.5771C>T	p.Ala1924Val	missense	Exon 28 of 47	ENSP00000352572.5	O95613-1
PCNT	ENST00000480896.5	TSL:1	c.5417C>T	p.Ala1806Val	missense	Exon 28 of 47	ENSP00000511989.1	O95613-2
PCNT	ENST00000695558.1		c.5804C>T	p.Ala1935Val	missense	Exon 29 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes

AF:

0.00597

AC:

909

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00830

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00894

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00596

AC:

962

AN:

161328

AF XY:

0.00592

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00687

Gnomad ASJ exome

AF:

0.00882

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00118

Gnomad NFE exome

AF:

0.00897

Gnomad OTH exome

AF:

0.00966

GnomAD4 exome

AF:

0.00703

AC:

9893

AN:

1406624

Hom.:

Cov.:

AF XY:

0.00704

AC XY:

4906

AN XY:

696660

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

32430

American (AMR)

AF:

0.00726

AC:

278

AN:

38302

Ashkenazi Jewish (ASJ)

AF:

0.00812

AC:

206

AN:

25374

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37098

South Asian (SAS)

AF:

0.00136

AC:

113

AN:

82984

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

37212

Middle Eastern (MID)

AF:

0.0180

AC:

AN:

4958

European-Non Finnish (NFE)

AF:

0.00793

AC:

8645

AN:

1089818

Other (OTH)

AF:

0.00761

AC:

445

AN:

58448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

639

1279

1918

2558

3197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.00597

AC:

909

AN:

152346

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

403

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41592

American (AMR)

AF:

0.00829

AC:

127

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00894

AC:

608

AN:

68032

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

187

234

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:

0.00722

Hom.:

Bravo

AF:

0.00672

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000549

AC:

ESP6500EA

AF:

0.00713

AC:

ExAC

AF:

0.00445

AC:

500

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Microcephalic osteodysplastic primordial dwarfism type II (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.11

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.021

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.11

PhyloP100

-1.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.21

REVEL

Benign

0.0050

Sift

Benign

0.78

Sift4G

Benign

0.67

Polyphen

0.0040

Vest4

0.046

MVP

0.27

MPC

0.33

ClinPred

0.00099

GERP RS

-5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.13

Mutation Taster

=95/5

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

Computational scores

Splicing

Publications

Other links and lift over