rs35881595

Positions:

• chr21-46436076-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.8924T>C​(p.Leu2975Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00194 in 1,613,046 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2975L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (17 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.75

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=0.007478386).
• BP6: Variant 21-46436076-T-C is Benign according to our data. Variant chr21-46436076-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 159682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46436076-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00603 (919/152290) while in subpopulation AFR AF= 0.0154 (639/41564). AF 95% confidence interval is 0.0144. There are 8 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.8924T>C	p.Leu2975Pro	missense_variant	39/47	ENST00000359568.10
PCNT	NM_001315529.2	c.8333T>C	p.Leu2778Pro	missense_variant	39/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.8924T>C	p.Leu2975Pro	missense_variant	39/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152172 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00292 AC: 720 AN: 246774 Hom.: 6 AF XY: 0.00251 AC XY: 336 AN XY: 134128

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00151 AC: 2205 AN: 1460756 Hom.: 17 Cov.: 33 AF XY: 0.00143 AC XY: 1039 AN XY: 726748

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000757

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00603 AC: 919 AN: 152290 Hom.: 8 Cov.: 33 AF XY: 0.00615 AC XY: 458 AN XY: 74480

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00218 Hom.: 2

Bravo AF: 0.00699

ESP6500AA AF: 0.0157 AC: 69

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.71
MPC		0.52
ClinPred		0.053	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.54

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: rs35881595; hg19: chr21-47855989;