rs6518289

chr21-46367087-T-Cchr21-46367087-T-A

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.3113T>C(p.Val1038Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,613,630 control chromosomes in the GnomAD database, including 610,688 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57696 hom., cov: 32)
  • Exomes 𝑓: 0.87 (552992 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.194

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=9.449875E-7).
• BP6: Variant 21-46367087-T-C is Benign according to our data. Variant chr21-46367087-T-C is described in ClinVar as [Benign]. Clinvar id is 159581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46367087-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.3113T>C	p.Val1038Ala	missense_variant	15/47	ENST00000359568.10
PCNT	NM_001315529.2	c.2759T>C	p.Val920Ala	missense_variant	15/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.3113T>C	p.Val1038Ala	missense_variant	15/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132358 AN: 152088 Hom.: 57659 Cov.: 32

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.875

GnomAD3 exomes AF: 0.853 AC: 212763 AN: 249528 Hom.: 90974 AF XY: 0.850 AC XY: 114896 AN XY: 135226

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.816

Gnomad SAS exome AF: 0.783

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.869 AC: 1270245 AN: 1461424 Hom.: 552992 Cov.: 64 AF XY: 0.866 AC XY: 629436 AN XY: 726984

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.833

Gnomad4 ASJ exome AF: 0.889

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.788

Gnomad4 FIN exome AF: 0.842

Gnomad4 NFE exome AF: 0.880

Gnomad4 OTH exome AF: 0.868

GnomAD4 genome AF: 0.870 AC: 132453 AN: 152206 Hom.: 57696 Cov.: 32 AF XY: 0.864 AC XY: 64292 AN XY: 74408

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.838

Gnomad4 ASJ AF: 0.876

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.788

Gnomad4 FIN AF: 0.842

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.876

Alfa AF: 0.872 Hom.: 48584

Bravo AF: 0.873

TwinsUK AF: 0.877 AC: 3253

ALSPAC AF: 0.883 AC: 3404

ESP6500AA AF: 0.898 AC: 3958

ESP6500EA AF: 0.875 AC: 7527

ExAC AF: 0.852 AC: 103477

Asia WGS AF: 0.800 AC: 2784 AN: 3478

EpiCase AF: 0.873

EpiControl AF: 0.874

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0040
Dann	Benign	0.35
DEOGEN2	Benign	0.031	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Benign	0.64	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.097
ClinPred		0.025	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.047

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: rs6518289; hg19: chr21-47787002; COSMIC: COSV64031868;