rs61735817

chr21-46427786-C-T

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.7485C>T(p.Ile2495=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,372 control chromosomes in the GnomAD database, including 2,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (194 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2418 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.02

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=-0.77).
• BP6: Variant 21-46427786-C-T is Benign according to our data. Variant chr21-46427786-C-T is described in ClinVar as [Benign]. Clinvar id is 138602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46427786-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.7485C>T	p.Ile2495=	synonymous_variant	34/47	ENST00000359568.10
PCNT	NM_001315529.2	c.7131C>T	p.Ile2377=	synonymous_variant	34/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.7485C>T	p.Ile2495=	synonymous_variant	34/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6312 AN: 152156 Hom.: 195 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0383

GnomAD3 exomes AF: 0.0431 AC: 10804 AN: 250542 Hom.: 286 AF XY: 0.0430 AC XY: 5834 AN XY: 135598

Gnomad AFR exome AF: 0.00864

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0572

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.0610

Gnomad OTH exome AF: 0.0460

GnomAD4 exome AF: 0.0537 AC: 78479 AN: 1461098 Hom.: 2418 Cov.: 33 AF XY: 0.0528 AC XY: 38345 AN XY: 726834

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0558

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0474

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152274 Hom.: 194 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74460

Gnomad4 AFR AF: 0.00979

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0850

Gnomad4 NFE AF: 0.0625

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0542 Hom.: 130

Bravo AF: 0.0359

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0542

EpiControl AF: 0.0535

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	-0.77
Cadd	Benign	0.39
Dann	Benign	0.42

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: rs61735817; hg19: chr21-47847700; COSMIC: COSV64033655; COSMIC: COSV64033655;