rs148384323

Positions:

• chr21-46425960-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006031.6(PCNT):​c.7309G>C​(p.Gly2437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -1.18

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021649718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.7309G>C	p.Gly2437Arg	missense_variant	33/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6955G>C	p.Gly2319Arg	missense_variant	33/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.7309G>C	p.Gly2437Arg	missense_variant	33/47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000545 AC: 137 AN: 251320 Hom.: 0 AF XY: 0.000545 AC XY: 74 AN XY: 135854

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000986

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1461776 Hom.: 0 Cov.: 33 AF XY: 0.00115 AC XY: 836 AN XY: 727188

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74334

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000627

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 02, 2017

- -

PCNT-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The PCNT c.7309G>C variant is predicted to result in the amino acid substitution p.Gly2437Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.098% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for an undocumented cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 31, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2437 of the PCNT protein (p.Gly2437Arg). This variant is present in population databases (rs148384323, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PCNT-related conditions. ClinVar contains an entry for this variant (Variation ID: 436217). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.9
DANN	Benign	0.50
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.010
Sift	Benign	0.099	T
Sift4G	Benign	0.070	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.29		Gain of helix (P = 0.0078);
MVP		0.26
MPC		0.16
ClinPred		0.65	D
GERP RS		-0.35
Varity_R		0.084
gMVP		0.043

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: rs148384323; hg19: chr21-47845874;