rs61735813

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006031.6(PCNT):c.6957T>G(p.Phe2319Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,609,758 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 12 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.0790

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044552684).

BP6

Variant 21-46418239-T-G is Benign according to our data. Variant chr21-46418239-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159646.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00132 (1918/1457374) while in subpopulation MID AF = 0.0052 (30/5766). AF 95% confidence interval is 0.00374. There are 12 homozygotes in GnomAdExome4. There are 967 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 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.6957T>G	p.Phe2319Leu	missense	Exon 31 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6603T>G	p.Phe2201Leu	missense	Exon 31 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.6957T>G	p.Phe2319Leu	missense	Exon 31 of 47	ENSP00000352572.5	O95613-1
PCNT	ENST00000480896.5	TSL:1	c.6603T>G	p.Phe2201Leu	missense	Exon 31 of 47	ENSP00000511989.1	O95613-2
PCNT	ENST00000695558.1		c.6990T>G	p.Phe2330Leu	missense	Exon 32 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00175

AC:

441

AN:

251296

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.0262

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000985

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00132

AC:

1918

AN:

1457374

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

967

AN XY:

725380

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33316

American (AMR)

AF:

0.00134

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0253

AC:

660

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000899

AC:

996

AN:

1108002

Other (OTH)

AF:

0.00262

AC:

158

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

173

260

346

433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00110

AC:

167

AN:

152384

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41596

American (AMR)

AF:

0.00124

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.00196

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00143

AC:

174

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephalic osteodysplastic primordial dwarfism type II (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.5

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.016

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.52

M_CAP

Benign

0.0069

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

PhyloP100

-0.079

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.81

REVEL

Benign

0.080

Sift

Benign

0.89

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.030

MutPred

0.088

Gain of helix (P = 0.0325)

MVP

0.23

MPC

0.094

ClinPred

0.0072

GERP RS

0.84

Varity_R

0.034

gMVP

0.12

Mutation Taster

=99/1

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