rs143511166

Positions:

• chr21-46425823-C-T
• chr21-46425823-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006031.6(PCNT):​c.7180-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,344 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: PCNT NM_006031.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003640
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.41

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-46425823-C-T is Benign according to our data. Variant chr21-46425823-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340528.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr21-46425823-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.7180-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000359568.10
PCNT	NM_001315529.2	c.6826-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.7180-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00162 AC: 406 AN: 250728 Hom.: 1 AF XY: 0.00163 AC XY: 221 AN XY: 135690

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00587

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00188 AC: 2750 AN: 1461130 Hom.: 6 Cov.: 33 AF XY: 0.00181 AC XY: 1318 AN XY: 726844

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00620

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74410

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.00123

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2015	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 15, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PCNT: BP4, BS2 -

Microcephalic osteodysplastic primordial dwarfism type II Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.010		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: rs143511166; hg19: chr21-47845737;