rs6518291

chr21-46401674-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):c.4915A>G(p.Ile1639Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,280 control chromosomes in the GnomAD database, including 44,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8761 hom., cov: 31)
  • Exomes 𝑓: 0.21 (36046 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7264406E-5).
• BP6: Variant 21-46401674-A-G is Benign according to our data. Variant chr21-46401674-A-G is described in ClinVar as [Benign]. Clinvar id is 159613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46401674-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.4915A>G	p.Ile1639Val	missense_variant	26/47	ENST00000359568.10
PCNT	NM_001315529.2	c.4561A>G	p.Ile1521Val	missense_variant	26/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.4915A>G	p.Ile1639Val	missense_variant	26/47	1	NM_006031.6	P2
PCNT	ENST00000480896.5	c.4561A>G	p.Ile1521Val	missense_variant	26/47	1		A2
PCNT	ENST00000695558.1	c.4948A>G	p.Ile1650Val	missense_variant	27/48			A2
PCNT	ENST00000703224.1	c.*4158A>G		3_prime_UTR_variant, NMD_transcript_variant	28/49

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46355 AN: 151522 Hom.: 8742 Cov.: 31

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.242 AC: 60698 AN: 251320 Hom.: 8350 AF XY: 0.239 AC XY: 32503 AN XY: 135832

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.212 AC: 309294 AN: 1461640 Hom.: 36046 Cov.: 35 AF XY: 0.214 AC XY: 155690 AN XY: 727140

Gnomad4 AFR exome AF: 0.555

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.306 AC: 46423 AN: 151640 Hom.: 8761 Cov.: 31 AF XY: 0.309 AC XY: 22923 AN XY: 74084

Gnomad4 AFR AF: 0.536

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.287

Alfa AF: 0.217 Hom.: 8782

Bravo AF: 0.312

TwinsUK AF: 0.187 AC: 693

ALSPAC AF: 0.188 AC: 723

ESP6500AA AF: 0.536 AC: 2361

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.249 AC: 30243

Asia WGS AF: 0.309 AC: 1071 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

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
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.18
Dann	Benign	0.12
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00049	N
LIST_S2	Benign	0.093	T
MetaRNN	Benign	0.000047	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.81	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.18
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.068
ClinPred		0.011	T
GERP RS		1.8
Varity_R		0.015
gMVP		0.020

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: rs6518291; hg19: chr21-47821588; COSMIC: COSV64027435;