21-46363740-C-G

Position:

• chr21-46363740-C-G

Variant summary

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

The ENST00000359568.10(PCNT):​c.2415C>G​(p.Ala805=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,614,106 control chromosomes in the GnomAD database, including 7,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3523 hom., cov: 33)
  • Exomes 𝑓: 0.026 (3645 hom.)
• Consequence: PCNT ENST00000359568.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.146

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=-0.66).
• BP6: Variant 21-46363740-C-G is Benign according to our data. Variant chr21-46363740-C-G is described in ClinVar as [Benign]. Clinvar id is 138616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46363740-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.2415C>G	p.Ala805=	synonymous_variant	14/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.2061C>G	p.Ala687=	synonymous_variant	14/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.2415C>G	p.Ala805=	synonymous_variant	14/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19579 AN: 152118 Hom.: 3520 Cov.: 33

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0498 AC: 12511 AN: 251384 Hom.: 1536 AF XY: 0.0450 AC XY: 6116 AN XY: 135876

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00364

Gnomad SAS exome AF: 0.0738

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0265 AC: 38739 AN: 1461870 Hom.: 3645 Cov.: 32 AF XY: 0.0267 AC XY: 19434 AN XY: 727242

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.0708

Gnomad4 FIN exome AF: 0.0203

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0453

GnomAD4 genome AF: 0.129 AC: 19619 AN: 152236 Hom.: 3523 Cov.: 33 AF XY: 0.126 AC XY: 9384 AN XY: 74430

Gnomad4 AFR AF: 0.406

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.0825

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0215 Hom.: 94

Bravo AF: 0.143

Asia WGS AF: 0.0920 AC: 318 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0156

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

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
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.4
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61407822; hg19: chr21-47783655;