rs33956783

Positions:

• chr21-46432135-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.03

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=0.003991008).
• BP6: Variant 21-46432135-G-A is Benign according to our data. Variant chr21-46432135-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46432135-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.8671G>A	p.Ala2891Thr	missense_variant	38/47	ENST00000359568.10
PCNT	NM_001315529.2	c.8160+157G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.8671G>A	p.Ala2891Thr	missense_variant	38/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1108 AN: 152274 Hom.: 5 Cov.: 34

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

GnomAD3 exomes AF: 0.00699 AC: 1748 AN: 250000 Hom.: 15 AF XY: 0.00685 AC XY: 927 AN XY: 135384

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 SAS exome AF: 0.00710

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.: 37 AF XY: 0.0108 AC XY: 7861 AN XY: 727078

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00729

Gnomad4 FIN exome AF: 0.00171

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00846

GnomAD4 genome AF: 0.00727 AC: 1108 AN: 152392 Hom.: 5 Cov.: 34 AF XY: 0.00682 AC XY: 508 AN XY: 74520

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.00483

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0111 Hom.: 19

Bravo AF: 0.00719

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.00667 AC: 810

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PCNT: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2015	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.013
DANN	Benign	0.63
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.047
Sift	Benign	0.63	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.058
MVP		0.24
MPC		0.079
ClinPred		0.0019	T
GERP RS		-9.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.045

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: rs33956783; hg19: chr21-47852049;