rs77075366

Positions:

• chr21-46427705-G-C

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.7404G>C​(p.Gln2468His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,908 control chromosomes in the GnomAD database, including 39 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (22 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (17 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.463

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=0.00375247).
• BP6: Variant 21-46427705-G-C is Benign according to our data. Variant chr21-46427705-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 159657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46427705-G-C is described in Lovd as [Benign]. Variant chr21-46427705-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00693 (1056/152338) while in subpopulation AFR AF= 0.0245 (1018/41562). AF 95% confidence interval is 0.0232. There are 22 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.7404G>C	p.Gln2468His	missense_variant	34/47	ENST00000359568.10
PCNT	NM_001315529.2	c.7050G>C	p.Gln2350His	missense_variant	34/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.7404G>C	p.Gln2468His	missense_variant	34/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152220 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00181 AC: 455 AN: 251246 Hom.: 5 AF XY: 0.00136 AC XY: 185 AN XY: 135844

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461570 Hom.: 17 Cov.: 32 AF XY: 0.000630 AC XY: 458 AN XY: 727088

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152338 Hom.: 22 Cov.: 33 AF XY: 0.00654 AC XY: 487 AN XY: 74496

Gnomad4 AFR AF: 0.0245

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00205 Hom.: 5

Bravo AF: 0.00798

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2017	- -
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)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	Mar 04, 2013	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
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. -

PCNT-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.031
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.37	B
Vest4		0.21
MutPred		0.20		Gain of helix (P = 0.0325);
MVP		0.58
MPC		0.11
ClinPred		0.0030	T
GERP RS		1.3
Varity_R		0.053
gMVP		0.21

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: rs77075366; hg19: chr21-47847619;