rs10222116

Positions:

• chr21-46413003-G-C
• chr21-46413003-G-A
• chr21-46413003-G-T

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.6150+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,414,308 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCNT NM_006031.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.316

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 (BayesDel_noAF=-0.83).
• BP6: Variant 21-46413003-G-C is Benign according to our data. Variant chr21-46413003-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 159629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46413003-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00103 (1455/1414308) while in subpopulation AFR AF= 0.0135 (428/31758). AF 95% confidence interval is 0.0124. There are 11 homozygotes in gnomad4_exome. There are 718 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.6150+11G>C		intron_variant		ENST00000359568.10
PCNT	NM_001315529.2	c.5796+11G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.6150+11G>C		intron_variant		1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1466 AN: 119418 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00841

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00318

Gnomad MID AF: 0.0144

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00425 AC: 941 AN: 221224 Hom.: 10 AF XY: 0.00354 AC XY: 426 AN XY: 120238

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.000411

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000444

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00103 AC: 1455 AN: 1414308 Hom.: 11 Cov.: 33 AF XY: 0.00102 AC XY: 718 AN XY: 703536

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00391

Gnomad4 EAS exome AF: 0.000209

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.000324

Gnomad4 NFE exome AF: 0.000539

Gnomad4 OTH exome AF: 0.00246

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0123 AC: 1471 AN: 119518 Hom.: 14 Cov.: 33 AF XY: 0.0121 AC XY: 708 AN XY: 58376

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00841

Gnomad4 EAS AF: 0.00353

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.00318

Gnomad4 NFE AF: 0.00349

Gnomad4 OTH AF: 0.0125

Alfa AF: 0.00135 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10222116; hg19: chr21-47832917; COSMIC: COSV64026201;