rs2839226

Positions:

• chr21-46366579-C-T
• chr21-46366579-C-A
• chr21-46366579-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000359568.10(PCNT):​c.2610-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,612,214 control chromosomes in the GnomAD database, including 494,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37953 hom., cov: 33)
  • Exomes 𝑓: 0.79 (456463 hom.)
• Consequence: PCNT ENST00000359568.10 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.361

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=-0.81).
• BP6: Variant 21-46366579-C-T is Benign according to our data. Variant chr21-46366579-C-T is described in ClinVar as [Benign]. Clinvar id is 159574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46366579-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.2610-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.2256-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.2610-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104855 AN: 151932 Hom.: 37948 Cov.: 33

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.714

GnomAD3 exomes AF: 0.756 AC: 188682 AN: 249504 Hom.: 72429 AF XY: 0.759 AC XY: 102622 AN XY: 135280

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.813

Gnomad SAS exome AF: 0.695

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.788 AC: 1150112 AN: 1460164 Hom.: 456463 Cov.: 39 AF XY: 0.785 AC XY: 570464 AN XY: 726542

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.773

Gnomad4 ASJ exome AF: 0.803

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.738

Gnomad4 NFE exome AF: 0.809

Gnomad4 OTH exome AF: 0.770

GnomAD4 genome AF: 0.690 AC: 104887 AN: 152050 Hom.: 37953 Cov.: 33 AF XY: 0.687 AC XY: 51066 AN XY: 74344

Gnomad4 AFR AF: 0.451

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.789

Gnomad4 EAS AF: 0.799

Gnomad4 SAS AF: 0.697

Gnomad4 FIN AF: 0.735

Gnomad4 NFE AF: 0.800

Gnomad4 OTH AF: 0.712

Alfa AF: 0.778 Hom.: 72460

Bravo AF: 0.684

Asia WGS AF: 0.691 AC: 2408 AN: 3478

EpiCase AF: 0.804

EpiControl AF: 0.804

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs2839226; hg19: chr21-47786494; COSMIC: COSV64031156;