rs61738290

Positions:

• chr21-46416836-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.6918T>C​(p.Ala2306=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0411 in 1,597,378 control chromosomes in the GnomAD database, including 1,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (150 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1616 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0220

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=-0.83).
• BP6: Variant 21-46416836-T-C is Benign according to our data. Variant chr21-46416836-T-C is described in ClinVar as [Benign]. Clinvar id is 159643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416836-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.6918T>C	p.Ala2306=	synonymous_variant	30/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6564T>C	p.Ala2188=	synonymous_variant	30/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.6918T>C	p.Ala2306=	synonymous_variant	30/47	1	NM_006031.6	ENSP00000352572	P2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5337 AN: 152176 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0501

GnomAD3 exomes AF: 0.0379 AC: 8655 AN: 228324 Hom.: 280 AF XY: 0.0381 AC XY: 4817 AN XY: 126276

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.0167

Gnomad FIN exome AF: 0.00753

Gnomad NFE exome AF: 0.0490

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0418 AC: 60364 AN: 1445084 Hom.: 1616 Cov.: 34 AF XY: 0.0418 AC XY: 30056 AN XY: 719330

Gnomad4 AFR exome AF: 0.0196

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.00950

Gnomad4 NFE exome AF: 0.0444

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0350 AC: 5335 AN: 152294 Hom.: 150 Cov.: 33 AF XY: 0.0326 AC XY: 2431 AN XY: 74462

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.0374

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0487

Alfa AF: 0.0518 Hom.: 71

Bravo AF: 0.0384

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0595

EpiControl AF: 0.0581

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.0
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61738290; hg19: chr21-47836750;