rs7279204

chr21-46388764-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):c.3487C>T(p.Arg1163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,613,632 control chromosomes in the GnomAD database, including 15,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1285 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14021 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.242

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005921036).
• BP6: Variant 21-46388764-C-T is Benign according to our data. Variant chr21-46388764-C-T is described in ClinVar as [Benign]. Clinvar id is 159589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46388764-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.3487C>T	p.Arg1163Cys	missense_variant	18/47	ENST00000359568.10
PCNT	NM_001315529.2	c.3133C>T	p.Arg1045Cys	missense_variant	18/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.3487C>T	p.Arg1163Cys	missense_variant	18/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18698 AN: 152082 Hom.: 1284 Cov.: 33

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.148 AC: 37018 AN: 250838 Hom.: 2993 AF XY: 0.151 AC XY: 20542 AN XY: 135686

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.134 AC: 195571 AN: 1461432 Hom.: 14021 Cov.: 33 AF XY: 0.137 AC XY: 99781 AN XY: 727042

Gnomad4 AFR exome AF: 0.0685

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.123 AC: 18718 AN: 152200 Hom.: 1285 Cov.: 33 AF XY: 0.129 AC XY: 9564 AN XY: 74418

Gnomad4 AFR AF: 0.0692

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.121

Alfa AF: 0.130 Hom.: 2179

Bravo AF: 0.118

TwinsUK AF: 0.128 AC: 475

ALSPAC AF: 0.121 AC: 466

ESP6500AA AF: 0.0654 AC: 288

ESP6500EA AF: 0.129 AC: 1110

ExAC AF: 0.147 AC: 17865

Asia WGS AF: 0.205 AC: 711 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.130

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	Eurofins Ntd Llc (ga)	Jul 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 14, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.099
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.46
ClinPred		0.063	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.16
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7279204; hg19: chr21-47808679; COSMIC: COSV64028879;