rs12481791

Positions:

• chr21-46428552-C-T
• chr21-46428552-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.7652C>T​(p.Ala2551Val) variant causes a missense change. The variant allele was found at a frequency of 0.0189 in 1,606,570 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 34)
  • Exomes 𝑓: 0.019 (339 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.87

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 -14 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 21-46428552-C-T is Benign according to our data. Variant chr21-46428552-C-T is described in ClinVar as [Benign]. Clinvar id is 138605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46428552-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2261/152382) while in subpopulation NFE AF= 0.0236 (1608/68036). AF 95% confidence interval is 0.0227. There are 27 homozygotes in gnomad4. There are 1096 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.7652C>T	p.Ala2551Val	missense_variant	35/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.7298C>T	p.Ala2433Val	missense_variant	35/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.7652C>T	p.Ala2551Val	missense_variant	35/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2260 AN: 152264 Hom.: 27 Cov.: 34

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0140 AC: 3302 AN: 235048 Hom.: 30 AF XY: 0.0143 AC XY: 1848 AN XY: 129600

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.00739

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00155

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0193 AC: 28095 AN: 1454188 Hom.: 339 Cov.: 33 AF XY: 0.0190 AC XY: 13768 AN XY: 723538

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00794

Gnomad4 ASJ exome AF: 0.00663

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0148 AC: 2261 AN: 152382 Hom.: 27 Cov.: 34 AF XY: 0.0147 AC XY: 1096 AN XY: 74522

Gnomad4 AFR AF: 0.00377

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0236

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0215 Hom.: 31

Bravo AF: 0.0138

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00365 AC: 16

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0140 AC: 1684

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PCNT: PP3, BS1, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 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. -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.75	N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Benign	0.043	D
Sift4G	Uncertain	0.049	D
Polyphen		0.26	B
Vest4		0.13
MPC		0.091
ClinPred		0.027	T
GERP RS		3.5
Varity_R		0.090
gMVP		0.023

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12481791; hg19: chr21-47848466;