21-46430570-G-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.7977G>C(p.Gln2659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,559,684 control chromosomes in the GnomAD database, including 228,653 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19204 hom., cov: 33)
  • Exomes 𝑓: 0.54 (209449 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.90

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=2.4640954E-6).
• BP6: Variant 21-46430570-G-C is Benign according to our data. Variant chr21-46430570-G-C is described in ClinVar as [Benign]. Clinvar id is 159670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46430570-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.7977G>C	p.Gln2659His	missense_variant	37/47	ENST00000359568.10
PCNT	NM_001315529.2	c.7623G>C	p.Gln2541His	missense_variant	37/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.7977G>C	p.Gln2659His	missense_variant	37/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74529 AN: 151918 Hom.: 19196 Cov.: 33

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.533

GnomAD3 exomes AF: 0.526 AC: 90059 AN: 171372 Hom.: 24287 AF XY: 0.533 AC XY: 48447 AN XY: 90846

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.529

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.543 AC: 764307 AN: 1407648 Hom.: 209449 Cov.: 58 AF XY: 0.545 AC XY: 379032 AN XY: 695260

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.651

Gnomad4 EAS exome AF: 0.673

Gnomad4 SAS exome AF: 0.535

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.547

Gnomad4 OTH exome AF: 0.542

GnomAD4 genome AF: 0.491 AC: 74577 AN: 152036 Hom.: 19204 Cov.: 33 AF XY: 0.489 AC XY: 36296 AN XY: 74300

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.499

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.530

Alfa AF: 0.524 Hom.: 6086

Bravo AF: 0.484

TwinsUK AF: 0.550 AC: 2041

ALSPAC AF: 0.544 AC: 2097

ESP6500AA AF: 0.342 AC: 1499

ESP6500EA AF: 0.557 AC: 4764

ExAC AF: 0.453 AC: 51092

Asia WGS AF: 0.571 AC: 1985 AN: 3478

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 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	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	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.0020
Dann	Benign	0.89
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.083
Sift	Benign	0.093	T
Sift4G	Uncertain	0.032	D
Polyphen		0.031	B
Vest4		0.066
MutPred		0.16		Loss of stability (P = 0.1486);
MPC		0.34
ClinPred		0.021	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.078

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: rs2070426; hg19: chr21-47850484; COSMIC: COSV64026155; COSMIC: COSV64026155;