rs57108405

Variant names:

• chr21-46416512-T-C
• rs57108405
• NM_006031.6:c.6594T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.6594T>C​(p.Gly2198Gly) 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
• Publications: 5 publications found

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]

PCNT Gene-Disease associations (from GenCC):

• microcephalic osteodysplastic primordial dwarfism type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 138625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PCNT	NM_006031.6	c.6594T>C	p.Gly2198Gly	synonymous_variant	Exon 30 of 47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6240T>C	p.Gly2080Gly	synonymous_variant	Exon 30 of 47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.6594T>C	p.Gly2198Gly	synonymous_variant	Exon 30 of 47	1	NM_006031.6	ENSP00000352572.5

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

GnomAD2 exomes AF: 0.0496 AC: 12447 AN: 250708 AF XY: 0.0452

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 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

African (AFR) AF: 0.433 AC: 14501 AN: 33480

American (AMR) AF: 0.0358 AC: 1602 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 359 AN: 26136

East Asian (EAS) AF: 0.00161 AC: 64 AN: 39700

South Asian (SAS) AF: 0.0726 AC: 6265 AN: 86256

European-Finnish (FIN) AF: 0.0199 AC: 1055 AN: 53070

Middle Eastern (MID) AF: 0.0414 AC: 239 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11915 AN: 1111990

Other (OTH) AF: 0.0463 AC: 2799 AN: 60392

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

African (AFR) AF: 0.409 AC: 16975 AN: 41506

American (AMR) AF: 0.0605 AC: 926 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5180

South Asian (SAS) AF: 0.0851 AC: 411 AN: 4832

European-Finnish (FIN) AF: 0.0219 AC: 233 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 847 AN: 68006

Other (OTH) AF: 0.117 AC: 248 AN: 2114

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57108405; hg19: chr21-47836426;