chr21-46432135-G-A

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.8671G>A(p.Ala2891Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,008 control chromosomes in the GnomAD database, including 130 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2891V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0073 ( 5 hom., cov: 34)

Exomes 𝑓: 0.011 ( 125 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.03

Publications

11 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=0.003991008).

BP6

Variant 21-46432135-G-A is Benign according to our data. Variant chr21-46432135-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138611.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 = 0.00727 (1108/152392) while in subpopulation NFE AF = 0.0127 (861/68044). AF 95% confidence interval is 0.012. There are 5 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.8671G>A	p.Ala2891Thr	missense	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8160+157G>A		intron	N/A	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.8671G>A	p.Ala2891Thr	missense	Exon 38 of 47	ENSP00000352572.5	O95613-1
PCNT	ENST00000480896.5	TSL:1	c.8160+157G>A		intron	N/A	ENSP00000511989.1	O95613-2
PCNT	ENST00000695558.1		c.8704G>A	p.Ala2902Thr	missense	Exon 39 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes

AF:

0.00728

AC:

1108

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00699

AC:

1748

AN:

250000

AF XY:

0.00685

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.00610

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00818

GnomAD4 exome

AF:

0.0111

AC:

16219

AN:

1461616

Hom.:

125

Cov.:

AF XY:

0.0108

AC XY:

7861

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33474

American (AMR)

AF:

0.00501

AC:

224

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00643

AC:

168

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00729

AC:

629

AN:

86250

European-Finnish (FIN)

AF:

0.00171

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0131

AC:

14540

AN:

1111984

Other (OTH)

AF:

0.00846

AC:

511

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

991

1981

2972

3962

4953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.00727

AC:

1108

AN:

152392

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

508

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00240

AC:

100

AN:

41602

American (AMR)

AF:

0.00483

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00559

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

861

AN:

68044

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0105

Hom.:

Bravo

AF:

0.00719

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.00667

AC:

810

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Microcephalic osteodysplastic primordial dwarfism type II (4)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.013

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.029

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.2

PhyloP100

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

REVEL

Benign

0.047

Sift

Benign

0.63

Sift4G

Benign

0.87

Polyphen

0.0010

Vest4

0.058

MVP

0.24

MPC

0.079

ClinPred

0.0019

GERP RS

-9.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.015

gMVP

0.045

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

Computational scores

Splicing

Publications

Other links and lift over