21-46346736-G-A

Position:

chr21-46346736-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006031.6(PCNT):c.721-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,591,548 control chromosomes in the GnomAD database, including 107,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8407 hom., cov: 34)

Exomes 𝑓: 0.37 ( 99318 hom. )

Consequence

PCNT
NM_006031.6 splice_region, intron

Scores

Splicing: ADA: 0.000007724

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.90

Variant links:

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]

PCNT links:

PCNT (HGNC:):

PCNT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 21-46346736-G-A is Benign according to our data. Variant chr21-46346736-G-A is described in ClinVar as [Benign]. Clinvar id is 159653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46346736-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6 linkuse as main transcript	c.721-7G>A		splice_region_variant, intron_variant		ENST00000359568.10	NP_006022.3	O95613-1
PCNT	NM_001315529.2 linkuse as main transcript	c.367-7G>A		splice_region_variant, intron_variant			NP_001302458.1	O95613-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10 linkuse as main transcript	c.721-7G>A		splice_region_variant, intron_variant		1	NM_006031.6	ENSP00000352572.5		O95613-1

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48768

AN:

152046

Hom.:

8407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.426

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.418

Gnomad EAS

AF:

0.401

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.357

GnomAD3 exomes

AF:

0.340

AC:

71850

AN:

211102

Hom.:

12731

AF XY:

0.345

AC XY:

39482

AN XY:

114292

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.427

Gnomad EAS exome

AF:

0.410

Gnomad SAS exome

AF:

0.310

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.382

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.369

AC:

530683

AN:

1439384

Hom.:

99318

Cov.:

AF XY:

0.368

AC XY:

262840

AN XY:

713858

show subpopulations

Gnomad4 AFR exome

AF:

0.207

Gnomad4 AMR exome

AF:

0.239

Gnomad4 ASJ exome

AF:

0.421

Gnomad4 EAS exome

AF:

0.416

Gnomad4 SAS exome

AF:

0.318

Gnomad4 FIN exome

AF:

0.339

Gnomad4 NFE exome

AF:

0.381

Gnomad4 OTH exome

AF:

0.361

GnomAD4 genome

AF:

0.321

AC:

48777

AN:

152164

Hom.:

8407

Cov.:

AF XY:

0.315

AC XY:

23451

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.211

Gnomad4 AMR

AF:

0.280

Gnomad4 ASJ

AF:

0.418

Gnomad4 EAS

AF:

0.401

Gnomad4 SAS

AF:

0.315

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.382

Gnomad4 OTH

AF:

0.356

Alfa

AF:

0.368

Hom.:

17087

Bravo

AF:

0.315

Asia WGS

AF:

0.344

AC:

1198

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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)	May 10, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.4

DANN

Benign

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000077

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over