rs575313866

chr21-46411888-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):c.5815C>T(p.Arg1939Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000817 in 1,575,856 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00081 (7 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0470

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=0.006488085).
• BP6: Variant 21-46411888-C-T is Benign according to our data. Variant chr21-46411888-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411888-C-T is described in Lovd as [Benign]. Variant chr21-46411888-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000906 (138/152332) while in subpopulation SAS AF= 0.00911 (44/4828). AF 95% confidence interval is 0.00698. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.5815C>T	p.Arg1939Trp	missense_variant	28/47	ENST00000359568.10
PCNT	NM_001315529.2	c.5461C>T	p.Arg1821Trp	missense_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.5815C>T	p.Arg1939Trp	missense_variant	28/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152214 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00216 AC: 404 AN: 186964 Hom.: 2 AF XY: 0.00277 AC XY: 288 AN XY: 104148

Gnomad AFR exome AF: 0.000570

Gnomad AMR exome AF: 0.000739

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00420

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000307

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000807 AC: 1149 AN: 1423524 Hom.: 7 Cov.: 34 AF XY: 0.00110 AC XY: 775 AN XY: 706810

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.000686

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.00923

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152332 Hom.: 1 Cov.: 34 AF XY: 0.00132 AC XY: 98 AN XY: 74486

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000605 Hom.: 0

Bravo AF: 0.000699

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00174 AC: 205

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely 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	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	This variant is associated with the following publications: (PMID: 30392784, 29483666) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 17, 2015	- -
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 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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.045
Sift	Benign	0.058	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.33	B
Vest4		0.29
MVP		0.60
MPC		0.16
ClinPred		0.029	T
GERP RS		1.3
Varity_R		0.087
gMVP		0.40

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: rs575313866; hg19: chr21-47831802; COSMIC: COSV105258439;