rs17371795

chr21-46435963-A-G

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.8811A>G(p.Thr2937=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,614,024 control chromosomes in the GnomAD database, including 13,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1192 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12745 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.80

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=-0.93).
• BP6: Variant 21-46435963-A-G is Benign according to our data. Variant chr21-46435963-A-G is described in ClinVar as [Benign]. Clinvar id is 95343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46435963-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.8811A>G	p.Thr2937=	synonymous_variant	39/47	ENST00000359568.10
PCNT	NM_001315529.2	c.8220A>G	p.Thr2740=	synonymous_variant	39/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.8811A>G	p.Thr2937=	synonymous_variant	39/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18024 AN: 152154 Hom.: 1193 Cov.: 33

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.142 AC: 35715 AN: 251106 Hom.: 2820 AF XY: 0.146 AC XY: 19763 AN XY: 135768

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.209

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.127 AC: 185224 AN: 1461752 Hom.: 12745 Cov.: 34 AF XY: 0.130 AC XY: 94552 AN XY: 727192

Gnomad4 AFR exome AF: 0.0662

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.118 AC: 18044 AN: 152272 Hom.: 1192 Cov.: 33 AF XY: 0.124 AC XY: 9257 AN XY: 74442

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.115

Alfa AF: 0.120 Hom.: 1461

Bravo AF: 0.114

Asia WGS AF: 0.203 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	-0.93
Cadd	Benign	0.40
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17371795; hg19: chr21-47855876; COSMIC: COSV64028891; COSMIC: COSV64028891;