rs113591604

chr21-46443816-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006031.6(PCNT):c.9707G>A(p.Arg3236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,720 control chromosomes in the GnomAD database, including 10 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (9 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 0.00600

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047527254).
• BP6: Variant 21-46443816-G-A is Benign according to our data. Variant chr21-46443816-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr21-46443816-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (362/152296) while in subpopulation NFE AF= 0.00409 (278/68014). AF 95% confidence interval is 0.00369. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.9707G>A	p.Arg3236Gln	missense_variant	45/47	ENST00000359568.10
PCNT	NM_001315529.2	c.9116G>A	p.Arg3039Gln	missense_variant	45/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.9707G>A	p.Arg3236Gln	missense_variant	45/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00220 AC: 552 AN: 251138 Hom.: 1 AF XY: 0.00218 AC XY: 296 AN XY: 135806

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00378 AC: 5530 AN: 1461424 Hom.: 9 Cov.: 31 AF XY: 0.00362 AC XY: 2630 AN XY: 727030

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00464

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74484

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00351 Hom.: 1

Bravo AF: 0.00242

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00226 AC: 274

EpiCase AF: 0.00442

EpiControl AF: 0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PCNT: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2018	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. -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2020	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 31, 2016

- -

PCNT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2021

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	0.095
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.2
Dann	Benign	0.69
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.062
Sift	Benign	0.58	T
Sift4G	Benign	0.29	T
Polyphen		0.84	P
Vest4		0.10
MVP		0.42
MPC		0.29
ClinPred		0.018	T
GERP RS		-0.84
Varity_R		0.026
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113591604; hg19: chr21-47863729; COSMIC: COSV100856312; COSMIC: COSV100856312;