chr21-46324213-G-T

Position:

• chr21-46324213-G-T

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.-16G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,606,990 control chromosomes in the GnomAD database, including 2,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (211 hom., cov: 35)
  • Exomes 𝑓: 0.057 (2662 hom.)
• Consequence: PCNT NM_006031.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135

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 (BayesDel_noAF=-0.71).
• BP6: Variant 21-46324213-G-T is Benign according to our data. Variant chr21-46324213-G-T is described in ClinVar as [Benign]. Clinvar id is 138617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46324213-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.-16G>T		5_prime_UTR_variant	1/47	ENST00000359568.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.-16G>T		5_prime_UTR_variant	1/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6577 AN: 152176 Hom.: 212 Cov.: 35

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0440 AC: 10480 AN: 238208 Hom.: 270 AF XY: 0.0439 AC XY: 5687 AN XY: 129464

Gnomad AFR exome AF: 0.00810

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0636

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0568 AC: 82568 AN: 1454696 Hom.: 2662 Cov.: 31 AF XY: 0.0557 AC XY: 40258 AN XY: 723282

Gnomad4 AFR exome AF: 0.00824

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0552

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0853

Gnomad4 NFE exome AF: 0.0642

Gnomad4 OTH exome AF: 0.0500

GnomAD4 genome AF: 0.0432 AC: 6575 AN: 152294 Hom.: 211 Cov.: 35 AF XY: 0.0423 AC XY: 3152 AN XY: 74466

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0858

Gnomad4 NFE AF: 0.0661

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.0355 Hom.: 47

Bravo AF: 0.0375

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2014

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. -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs138595914; hg19: chr21-47744127; COSMIC: COSV52449400; COSMIC: COSV52449400;