21-46385858-T-C

Position:

• chr21-46385858-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006031.6(PCNT):​c.3339T>C​(p.Ser1113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,614,146 control chromosomes in the GnomAD database, including 1,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (100 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1565 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.537

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-46385858-T-C is Benign according to our data. Variant chr21-46385858-T-C is described in ClinVar as [Benign]. Clinvar id is 159585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46385858-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.537 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4659/152312) while in subpopulation NFE AF= 0.0486 (3305/68022). AF 95% confidence interval is 0.0472. There are 100 homozygotes in gnomad4. There are 2189 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 100 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.3339T>C	p.Ser1113=	synonymous_variant	17/47	ENST00000359568.10
PCNT	NM_001315529.2	c.2985T>C	p.Ser995=	synonymous_variant	17/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.3339T>C	p.Ser1113=	synonymous_variant	17/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4660 AN: 152194 Hom.: 99 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0251

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0486

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0355 AC: 8923 AN: 251494 Hom.: 208 AF XY: 0.0368 AC XY: 4996 AN XY: 135920

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.0320

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0492

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0432 AC: 63162 AN: 1461834 Hom.: 1565 Cov.: 32 AF XY: 0.0433 AC XY: 31484 AN XY: 727220

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0443

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.0342

Gnomad4 FIN exome AF: 0.0401

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0399

GnomAD4 genome AF: 0.0306 AC: 4659 AN: 152312 Hom.: 100 Cov.: 33 AF XY: 0.0294 AC XY: 2189 AN XY: 74472

Gnomad4 AFR AF: 0.00767

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0486

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0441 Hom.: 83

Bravo AF: 0.0282

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0467

EpiControl AF: 0.0424

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:3

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 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	-0.90
CADD	Benign	0.67
DANN	Benign	0.40

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: rs61735805; hg19: chr21-47805773;