rs34813667

chr21-46411952-G-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.5879G>A(p.Arg1960Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,597,508 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1960W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (115 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (115 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.123

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=0.0021196902).
• BP6: Variant 21-46411952-G-A is Benign according to our data. Variant chr21-46411952-G-A is described in ClinVar as [Benign]. Clinvar id is 159626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411952-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.5879G>A	p.Arg1960Gln	missense_variant	28/47	ENST00000359568.10
PCNT	NM_001315529.2	c.5525G>A	p.Arg1842Gln	missense_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.5879G>A	p.Arg1960Gln	missense_variant	28/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3044 AN: 152192 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00516 AC: 1145 AN: 222012 Hom.: 47 AF XY: 0.00360 AC XY: 444 AN XY: 123326

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00224 AC: 3232 AN: 1445198 Hom.: 115 Cov.: 34 AF XY: 0.00195 AC XY: 1402 AN XY: 719320

Gnomad4 AFR exome AF: 0.0749

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00410

GnomAD4 genome AF: 0.0200 AC: 3046 AN: 152310 Hom.: 115 Cov.: 33 AF XY: 0.0186 AC XY: 1387 AN XY: 74488

Gnomad4 AFR AF: 0.0692

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00337 Hom.: 3

Bravo AF: 0.0237

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0552 AC: 241

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00595 AC: 715

Asia WGS AF: 0.00520 AC: 19 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.54
Dann	Benign	0.69
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.029
Sift	Benign	0.36	T
Sift4G	Benign	0.90	T
Polyphen		0.29	B
Vest4		0.18
MVP		0.25
MPC		0.10
ClinPred		0.0033	T
GERP RS		-8.5
Varity_R		0.016
gMVP		0.057

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: rs34813667; hg19: chr21-47831866;