rs35940413

Positions:

• chr21-46411595-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.5522A>G​(p.Asn1841Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,612,692 control chromosomes in the GnomAD database, including 19,522 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5452 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14070 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.395

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=2.9724836E-4).
• BP6: Variant 21-46411595-A-G is Benign according to our data. Variant chr21-46411595-A-G is described in ClinVar as [Benign]. Clinvar id is 95336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411595-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.5522A>G	p.Asn1841Ser	missense_variant	28/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.5168A>G	p.Asn1723Ser	missense_variant	28/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.5522A>G	p.Asn1841Ser	missense_variant	28/47	1	NM_006031.6	ENSP00000352572	P2
PCNT	ENST00000480896.5	c.5168A>G	p.Asn1723Ser	missense_variant	28/47	1		ENSP00000511989	A2
PCNT	ENST00000695558.1	c.5555A>G	p.Asn1852Ser	missense_variant	29/48			ENSP00000512015	A2
PCNT	ENST00000703224.1	c.*4765A>G		3_prime_UTR_variant, NMD_transcript_variant	30/49			ENSP00000515242

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32584 AN: 151970 Hom.: 5447 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00582

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.213

GnomAD3 exomes AF: 0.133 AC: 32782 AN: 247286 Hom.: 3307 AF XY: 0.128 AC XY: 17288 AN XY: 134712

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.00311

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.123 AC: 179693 AN: 1460598 Hom.: 14070 Cov.: 34 AF XY: 0.122 AC XY: 88755 AN XY: 726638

Gnomad4 AFR exome AF: 0.485

Gnomad4 AMR exome AF: 0.0904

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.00189

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.214 AC: 32621 AN: 152094 Hom.: 5452 Cov.: 33 AF XY: 0.209 AC XY: 15550 AN XY: 74370

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.00583

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.215

Alfa AF: 0.146 Hom.: 2001

Bravo AF: 0.227

TwinsUK AF: 0.106 AC: 394

ALSPAC AF: 0.105 AC: 404

ESP6500AA AF: 0.458 AC: 2018

ESP6500EA AF: 0.130 AC: 1114

ExAC AF: 0.139 AC: 16895

Asia WGS AF: 0.114 AC: 396 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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)	Aug 07, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

PCNT-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.074
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.41
DANN	Benign	0.17
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.065
ClinPred		0.0043	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.017
gMVP		0.074

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: rs35940413; hg19: chr21-47831509; COSMIC: COSV64027443;