21-46416512-T-C

Position:

• chr21-46416512-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.6594T>C​(p.Gly2198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,613,746 control chromosomes in the GnomAD database, including 7,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3587 hom., cov: 32)
  • Exomes 𝑓: 0.027 (3744 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.35

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46416512-T-C is Benign according to our data. Variant chr21-46416512-T-C is described in ClinVar as [Benign]. Clinvar id is 138625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416512-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.6594T>C	p.Gly2198=	synonymous_variant	30/47	ENST00000359568.10
PCNT	NM_001315529.2	c.6240T>C	p.Gly2080=	synonymous_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.6594T>C	p.Gly2198=	synonymous_variant	30/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19700 AN: 152114 Hom.: 3583 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0496 AC: 12447 AN: 250708 Hom.: 1547 AF XY: 0.0452 AC XY: 6137 AN XY: 135798

Gnomad AFR exome AF: 0.420

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00310

Gnomad SAS exome AF: 0.0754

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0265 AC: 38799 AN: 1461514 Hom.: 3744 Cov.: 34 AF XY: 0.0268 AC XY: 19469 AN XY: 727074

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00161

Gnomad4 SAS exome AF: 0.0726

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0463

GnomAD4 genome AF: 0.130 AC: 19740 AN: 152232 Hom.: 3587 Cov.: 32 AF XY: 0.127 AC XY: 9441 AN XY: 74412

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.0851

Gnomad4 FIN AF: 0.0219

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0602 Hom.: 780

Bravo AF: 0.144

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.092
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs57108405; hg19: chr21-47836426;