rs201185279

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006031.6(PCNT):c.7459C>G(p.Leu2487Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2487Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.896

Publications

6 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054993033).

BP6

Variant 21-46427760-C-G is Benign according to our data. Variant chr21-46427760-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211882.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000197 (30/152324) while in subpopulation EAS AF = 0.00521 (27/5184). AF 95% confidence interval is 0.00368. There are 1 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.7459C>G	p.Leu2487Val	missense	Exon 34 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7105C>G	p.Leu2369Val	missense	Exon 34 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.7459C>G	p.Leu2487Val	missense	Exon 34 of 47	ENSP00000352572.5	O95613-1
PCNT	ENST00000480896.5	TSL:1	c.7105C>G	p.Leu2369Val	missense	Exon 34 of 47	ENSP00000511989.1	O95613-2
PCNT	ENST00000695558.1		c.7492C>G	p.Leu2498Val	missense	Exon 35 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000434

AC:

109

AN:

251100

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00593

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461420

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00355

AC:

141

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.0000828

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000197

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00521

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.00

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000544

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Microcephalic osteodysplastic primordial dwarfism type II (1)

PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.50

M_CAP

Benign

0.013

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PhyloP100

0.90

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.3

REVEL

Benign

0.070

Sift

Uncertain

0.025

Sift4G

Uncertain

0.023

Polyphen

0.86

Vest4

0.29

MVP

0.32

MPC

0.083

ClinPred

0.051

GERP RS

3.6

Varity_R

0.070

gMVP

0.040

Mutation Taster

=96/4

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