rs149623054

Positions:

• chr21-46357070-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006031.6(PCNT):​c.2033A>G​(p.Lys678Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,614,174 control chromosomes in the GnomAD database, including 5 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 0.00098 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00078 (4 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.312

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004591584).
• BP6: Variant 21-46357070-A-G is Benign according to our data. Variant chr21-46357070-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281569.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr21-46357070-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000985 (150/152342) while in subpopulation SAS AF= 0.00477 (23/4824). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.2033A>G	p.Lys678Arg	missense_variant	13/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.1679A>G	p.Lys560Arg	missense_variant	13/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.2033A>G	p.Lys678Arg	missense_variant	13/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152224 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00169 AC: 425 AN: 251482 Hom.: 1 AF XY: 0.00190 AC XY: 258 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00575

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000784 AC: 1146 AN: 1461832 Hom.: 4 Cov.: 32 AF XY: 0.000908 AC XY: 660 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00545

Gnomad4 FIN exome AF: 0.00749

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152342 Hom.: 1 Cov.: 34 AF XY: 0.00142 AC XY: 106 AN XY: 74494

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00838

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00161 AC: 196

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 07, 2016

- -

PCNT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 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). -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.026
Sift	Benign	0.47	T
Sift4G	Benign	0.54	T
Polyphen		0.024	B
Vest4		0.061
MVP		0.37
MPC		0.26
ClinPred		0.019	T
GERP RS		-1.3
Varity_R		0.061
gMVP		0.020

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: rs149623054; hg19: chr21-47776985; COSMIC: COSV100856315; COSMIC: COSV100856315;