rs35147998

chr21-46432171-G-Achr21-46432171-G-Tchr21-46432171-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):c.8707G>A(p.Ala2903Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0707 in 1,613,078 control chromosomes in the GnomAD database, including 4,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. A2903P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.056 (305 hom., cov: 34)
  • Exomes 𝑓: 0.072 (4072 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019298196).
• BP6: Variant 21-46432171-G-A is Benign according to our data. Variant chr21-46432171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46432171-G-A is described in Lovd as [Benign]. Variant chr21-46432171-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.8707G>A	p.Ala2903Thr	missense_variant	38/47	ENST00000359568.10
PCNT	NM_001315529.2	c.8160+193G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.8707G>A	p.Ala2903Thr	missense_variant	38/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8584 AN: 152250 Hom.: 305 Cov.: 34

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0713

GnomAD3 exomes AF: 0.0610 AC: 15089 AN: 247396 Hom.: 571 AF XY: 0.0619 AC XY: 8323 AN XY: 134364

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0892

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.0433

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0828

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0722 AC: 105536 AN: 1460710 Hom.: 4072 Cov.: 37 AF XY: 0.0715 AC XY: 51964 AN XY: 726584

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.0368

Gnomad4 ASJ exome AF: 0.0867

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.0760

Gnomad4 NFE exome AF: 0.0796

Gnomad4 OTH exome AF: 0.0638

GnomAD4 genome AF: 0.0563 AC: 8582 AN: 152368 Hom.: 305 Cov.: 34 AF XY: 0.0560 AC XY: 4170 AN XY: 74502

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.0596

Gnomad4 ASJ AF: 0.0835

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.0418

Gnomad4 FIN AF: 0.0741

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0769 Hom.: 795

Bravo AF: 0.0533

TwinsUK AF: 0.0841 AC: 312

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0828 AC: 712

ExAC AF: 0.0612 AC: 7432

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0819

EpiControl AF: 0.0838

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

PCNT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	12
Dann	Benign	0.53
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.083
Sift	Benign	0.23	T
Sift4G	Benign	0.46	T
Polyphen		0.089	B
Vest4		0.056
MPC		0.36
ClinPred		0.017	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.058

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

LitVar

Other links and lift over

dbSNP: rs35147998; hg19: chr21-47852085; COSMIC: COSV64025476; COSMIC: COSV64025476;