chr21-46440080-C-T

Variant names:

• chr21-46440080-C-T
• rs200348425
• NM_006031.6:c.9274-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.9274-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00391 in 1,614,030 control chromosomes in the GnomAD database, including 68 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 0.0033 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (62 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Scores: Splicing: ADA: 0.01661
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.79
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 21-46440080-C-T is Benign according to our data. Variant chr21-46440080-C-T is described in ClinVar as Benign. ClinVar VariationId is 159690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00329 (501/152298) while in subpopulation SAS AF = 0.0263 (127/4826). AF 95% confidence interval is 0.0226. There are 6 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.9274-3C>T		splice_region intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.8683-3C>T		splice_region intron	N/A	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.9274-3C>T		splice_region intron	N/A	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.8683-3C>T		splice_region intron	N/A	ENSP00000511989.1
	PCNT	ENST00000695537.1		n.334C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152180 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00595 AC: 1493 AN: 251050 AF XY: 0.00753

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00397 AC: 5803 AN: 1461732 Hom.: 62 Cov.: 33 AF XY: 0.00482 AC XY: 3502 AN XY: 727178

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.00255 AC: 114 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 366 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0249 AC: 2147 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53326

Middle Eastern (MID) AF: 0.0313 AC: 180 AN: 5760

European-Non Finnish (NFE) AF: 0.00233 AC: 2590 AN: 1111976

Other (OTH) AF: 0.00623 AC: 376 AN: 60384

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152298 Hom.: 6 Cov.: 33 AF XY: 0.00340 AC XY: 253 AN XY: 74470

African (AFR) AF: 0.000409 AC: 17 AN: 41550

American (AMR) AF: 0.00372 AC: 57 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68028

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00367 Hom.: 2

Bravo AF: 0.00272

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00533

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:3

Jan 06, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jun 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

Sep 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.15		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: rs200348425; hg19: chr21-47859993; COSMIC: COSV64030227; COSMIC: COSV64030227;