rs144471022

Positions:

• chr21-46416552-C-T

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.6634C>T​(p.Arg2212Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,612,910 control chromosomes in the GnomAD database, including 44 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (38 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.488

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=0.0044667125).
• BP6: Variant 21-46416552-C-T is Benign according to our data. Variant chr21-46416552-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416552-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0049 (746/152330) while in subpopulation NFE AF= 0.00491 (334/68028). AF 95% confidence interval is 0.00448. There are 6 homozygotes in gnomad4. There are 431 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.6634C>T	p.Arg2212Trp	missense_variant	30/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6280C>T	p.Arg2094Trp	missense_variant	30/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.6634C>T	p.Arg2212Trp	missense_variant	30/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152212 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00537 AC: 1344 AN: 250226 Hom.: 11 AF XY: 0.00554 AC XY: 752 AN XY: 135658

Gnomad AFR exome AF: 0.000503

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00510 AC: 7454 AN: 1460580 Hom.: 38 Cov.: 34 AF XY: 0.00502 AC XY: 3649 AN XY: 726568

Gnomad4 AFR exome AF: 0.000749

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00532

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.00491

Gnomad4 OTH exome AF: 0.00466

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152330 Hom.: 6 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74480

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00447 Hom.: 2

Bravo AF: 0.00297

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00508 AC: 617

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 05, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PCNT: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2018	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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 05, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.061
Sift	Benign	0.036	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.19
MVP		0.51
MPC		0.13
ClinPred		0.019	T
GERP RS		-2.7
Varity_R		0.042
gMVP		0.19

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: rs144471022; hg19: chr21-47836466;