rs139432601

Positions:

• chr21-46397393-C-G

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.4345C>G​(p.Gln1449Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,208 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (49 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.17

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=0.005584389).
• BP6: Variant 21-46397393-C-G is Benign according to our data. Variant chr21-46397393-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 159601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46397393-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00378 (576/152362) while in subpopulation NFE AF= 0.00698 (475/68036). AF 95% confidence interval is 0.00646. There are 5 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.4345C>G	p.Gln1449Glu	missense_variant	22/47	ENST00000359568.10
PCNT	NM_001315529.2	c.3991C>G	p.Gln1331Glu	missense_variant	22/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.4345C>G	p.Gln1449Glu	missense_variant	22/47	1	NM_006031.6	P2
PCNT	ENST00000480896.5	c.3991C>G	p.Gln1331Glu	missense_variant	22/47	1		A2
PCNT	ENST00000695558.1	c.4378C>G	p.Gln1460Glu	missense_variant	23/48			A2
PCNT	ENST00000703224.1	c.*3588C>G		3_prime_UTR_variant, NMD_transcript_variant	24/49

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 576 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00344 AC: 864 AN: 251342 Hom.: 7 AF XY: 0.00364 AC XY: 495 AN XY: 135874

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00610 AC: 8913 AN: 1461846 Hom.: 49 Cov.: 32 AF XY: 0.00590 AC XY: 4288 AN XY: 727218

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.000862

Gnomad4 NFE exome AF: 0.00729

Gnomad4 OTH exome AF: 0.00669

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00309 AC XY: 230 AN XY: 74506

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00698

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00572 Hom.: 4

Bravo AF: 0.00377

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PCNT: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 03, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2017	- -

PCNT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2019

This variant is classified as likely 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	0.099
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D
Sift4G	Benign	0.26	T
Polyphen		0.69	P
Vest4		0.12
MVP		0.49
MPC		0.14
ClinPred		0.010	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.023

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: rs139432601; hg19: chr21-47817307; COSMIC: COSV100856262;