rs3737438

chr21-46391357-C-Tchr21-46391357-C-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.4197C>T(p.Asp1399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,550,058 control chromosomes in the GnomAD database, including 105,254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8443 hom., cov: 33)
  • Exomes 𝑓: 0.37 (96811 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.50

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 21-46391357-C-T is Benign according to our data. Variant chr21-46391357-C-T is described in ClinVar as [Benign]. Clinvar id is 159597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46391357-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.4197C>T	p.Asp1399=	synonymous_variant	21/47	ENST00000359568.10
PCNT	NM_001315529.2	c.3843C>T	p.Asp1281=	synonymous_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.4197C>T	p.Asp1399=	synonymous_variant	21/47	1	NM_006031.6	P2
PCNT	ENST00000480896.5	c.3843C>T	p.Asp1281=	synonymous_variant	21/47	1		A2
PCNT	ENST00000695558.1	c.4197C>T	p.Asp1399=	synonymous_variant	21/48			A2
PCNT	ENST00000703224.1	c.*3440C>T		3_prime_UTR_variant, NMD_transcript_variant	23/49

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49013 AN: 151970 Hom.: 8445 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.338 AC: 51576 AN: 152382 Hom.: 9147 AF XY: 0.343 AC XY: 27881 AN XY: 81344

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.414

Gnomad SAS exome AF: 0.301

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.369 AC: 516293 AN: 1397970 Hom.: 96811 Cov.: 41 AF XY: 0.368 AC XY: 254034 AN XY: 689500

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.391

Gnomad4 EAS exome AF: 0.437

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.342

Gnomad4 NFE exome AF: 0.381

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.322 AC: 49018 AN: 152088 Hom.: 8443 Cov.: 33 AF XY: 0.317 AC XY: 23549 AN XY: 74338

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.357

Alfa AF: 0.355 Hom.: 6799

Bravo AF: 0.317

Asia WGS AF: 0.331 AC: 1153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2016	- -

not provided Benign:2

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

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.21
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs3737438; hg19: chr21-47811272; COSMIC: COSV64025595;