Genetic Variant PCNT:p.Ala2996Ala (chr21-46436140-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006031.6(PCNT):c.8988C>T(p.Ala2996Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 1,607,646 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2996A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 87 hom., cov: 33)

Exomes 𝑓: 0.036 ( 1088 hom. )

Consequence

PCNT
NM_006031.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.98

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 21-46436140-C-T is Benign according to our data. Variant chr21-46436140-C-T is described in ClinVar as Benign. ClinVar VariationId is 95344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.98 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0265 (4038/152342) while in subpopulation NFE AF = 0.04 (2720/68030). AF 95% confidence interval is 0.0387. There are 87 homozygotes in GnomAd4. There are 1877 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 87 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.8988C>T	p.Ala2996Ala	synonymous	Exon 39 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8397C>T	p.Ala2799Ala	synonymous	Exon 39 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.8988C>T	p.Ala2996Ala	synonymous	Exon 39 of 47	ENSP00000352572.5	O95613-1
PCNT	ENST00000480896.5	TSL:1	c.8397C>T	p.Ala2799Ala	synonymous	Exon 39 of 47	ENSP00000511989.1	O95613-2
PCNT	ENST00000695558.1		c.9021C>T	p.Ala3007Ala	synonymous	Exon 40 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4040

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00697

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00910

Gnomad FIN

AF:

0.0230

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0400

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0267

AC:

6271

AN:

235178

AF XY:

0.0266

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0488

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0404

Gnomad OTH exome

AF:

0.0305

GnomAD4 exome

AF:

0.0358

AC:

52152

AN:

1455304

Hom.:

1088

Cov.:

AF XY:

0.0352

AC XY:

25484

AN XY:

724322

show subpopulations

African (AFR)

AF:

0.00604

AC:

202

AN:

33462

American (AMR)

AF:

0.0174

AC:

776

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

1235

AN:

26100

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39690

South Asian (SAS)

AF:

0.00997

AC:

860

AN:

86234

European-Finnish (FIN)

AF:

0.0256

AC:

1216

AN:

47430

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.0412

AC:

45800

AN:

1111768

Other (OTH)

AF:

0.0326

AC:

1963

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3007

6014

9022

12029

15036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1648

3296

4944

6592

8240

<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:

0.0265

AC:

4038

AN:

152342

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1877

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00695

AC:

289

AN:

41588

American (AMR)

AF:

0.0241

AC:

369

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00890

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0230

AC:

244

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0400

AC:

2720

AN:

68030

Other (OTH)

AF:

0.0322

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

208

416

625

833

1041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0281

Hom.:

Bravo

AF:

0.0259

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.13

(source)

DANN

Benign

0.68

PhyloP100

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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