rs2839260

Variant names:

• chr21-46440851-T-C
• rs2839260
• NM_006031.6:c.9394-4T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.9394-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,579,672 control chromosomes in the GnomAD database, including 19,696 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 0.14 (1659 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18037 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002942
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0740
• Publications: 9 publications found

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]

PCNT Gene-Disease associations (from GenCC):

• microcephalic osteodysplastic primordial dwarfism type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-46440851-T-C is Benign according to our data. Variant chr21-46440851-T-C is described in ClinVar as [Benign]. Clinvar id is 159692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6	c.9394-4T>C		splice_region_variant, intron_variant	Intron 42 of 46	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.8803-4T>C		splice_region_variant, intron_variant	Intron 42 of 46		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.9394-4T>C		splice_region_variant, intron_variant	Intron 42 of 46	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21325 AN: 152140 Hom.: 1661 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.0947

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.124 AC: 31086 AN: 250258 AF XY: 0.125

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0745

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0156

Gnomad FIN exome AF: 0.0953

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.154 AC: 219537 AN: 1427414 Hom.: 18037 Cov.: 27 AF XY: 0.152 AC XY: 108087 AN XY: 712516

African (AFR) AF: 0.139 AC: 4566 AN: 32760

American (AMR) AF: 0.0789 AC: 3523 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4174 AN: 25906

East Asian (EAS) AF: 0.0130 AC: 514 AN: 39542

South Asian (SAS) AF: 0.0880 AC: 7529 AN: 85532

European-Finnish (FIN) AF: 0.100 AC: 5341 AN: 53294

Middle Eastern (MID) AF: 0.135 AC: 768 AN: 5692

European-Non Finnish (NFE) AF: 0.171 AC: 184755 AN: 1080822

Other (OTH) AF: 0.141 AC: 8367 AN: 59188

GnomAD4 genome AF: 0.140 AC: 21326 AN: 152258 Hom.: 1659 Cov.: 33 AF XY: 0.134 AC XY: 9985 AN XY: 74446

African (AFR) AF: 0.139 AC: 5761 AN: 41538

American (AMR) AF: 0.116 AC: 1768 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5188

South Asian (SAS) AF: 0.0813 AC: 392 AN: 4824

European-Finnish (FIN) AF: 0.0947 AC: 1005 AN: 10610

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11321 AN: 68012

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.160 Hom.: 2953

Bravo AF: 0.142

Asia WGS AF: 0.0590 AC: 206 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.67
PhyloP100		0.074
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs2839260; hg19: chr21-47860764;