rs143796569

chr21-46397402-G-A

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.4354G>A(p.Gly1452Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,614,170 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1452G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (25 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.16

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=0.008995593).
• BP6: Variant 21-46397402-G-A is Benign according to our data. Variant chr21-46397402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 159602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46397402-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00192 (292/152332) while in subpopulation SAS AF= 0.0162 (78/4824). AF 95% confidence interval is 0.0133. There are 2 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.4354G>A	p.Gly1452Arg	missense_variant	22/47	ENST00000359568.10
PCNT	NM_001315529.2	c.4000G>A	p.Gly1334Arg	missense_variant	22/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.4354G>A	p.Gly1452Arg	missense_variant	22/47	1	NM_006031.6	P2
PCNT	ENST00000480896.5	c.4000G>A	p.Gly1334Arg	missense_variant	22/47	1		A2
PCNT	ENST00000695558.1	c.4387G>A	p.Gly1463Arg	missense_variant	23/48			A2
PCNT	ENST00000703224.1	c.*3597G>A		3_prime_UTR_variant, NMD_transcript_variant	24/49

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00283 AC: 711 AN: 251336 Hom.: 6 AF XY: 0.00351 AC XY: 477 AN XY: 135878

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00333 AC: 4862 AN: 1461838 Hom.: 25 Cov.: 32 AF XY: 0.00360 AC XY: 2621 AN XY: 727218

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74486

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00316 AC: 384

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 17, 2015	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PCNT: BP4, BS1, BS2 -

Intellectual disability Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Gly1452Arg variant in PCNT has been identified in the compound heterozygous state in an individual with intellectual disability (PMID: 23033978), but has also been identified in >1% of South Asian chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.11	T
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.23		Gain of MoRF binding (P = 0.0334);
MVP		0.72
MPC		0.48
ClinPred		0.036	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.043

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143796569; hg19: chr21-47817316;