rs34151633

chr21-46416489-T-C

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.6571T>C(p.Ser2191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,614,058 control chromosomes in the GnomAD database, including 1,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. S2191Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.034 (147 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1597 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0120

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=0.0026471317).
• BP6: Variant 21-46416489-T-C is Benign according to our data. Variant chr21-46416489-T-C is described in ClinVar as [Benign]. Clinvar id is 159634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416489-T-C is described in Lovd as [Benign]. Variant chr21-46416489-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.6571T>C	p.Ser2191Pro	missense_variant	30/47	ENST00000359568.10
PCNT	NM_001315529.2	c.6217T>C	p.Ser2073Pro	missense_variant	30/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.6571T>C	p.Ser2191Pro	missense_variant	30/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5164 AN: 152216 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0369 AC: 9263 AN: 251262 Hom.: 297 AF XY: 0.0373 AC XY: 5067 AN XY: 135892

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.0493

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0412 AC: 60161 AN: 1461724 Hom.: 1597 Cov.: 34 AF XY: 0.0412 AC XY: 29941 AN XY: 727186

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.0310

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.00873

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0452

GnomAD4 genome AF: 0.0339 AC: 5162 AN: 152334 Hom.: 147 Cov.: 32 AF XY: 0.0315 AC XY: 2346 AN XY: 74486

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.0451

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0521 Hom.: 492

Bravo AF: 0.0373

TwinsUK AF: 0.0413 AC: 153

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.0560 AC: 482

ExAC AF: 0.0360 AC: 4367

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0589

EpiControl AF: 0.0580

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

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

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	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.025
Sift	Benign	0.25	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.097
MPC		0.34
ClinPred		0.0035	T
GERP RS		0.73
Varity_R		0.13
gMVP		0.15

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: rs34151633; hg19: chr21-47836403; COSMIC: COSV64028289; COSMIC: COSV64028289;