21-46418786-C-T

Variant names:

• chr21-46418786-C-T
• rs2268524
• NM_006031.6:c.7024+480C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006031.6(PCNT):​c.7024+480C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,202 control chromosomes in the GnomAD database, including 2,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2938 hom., cov: 33)
• Consequence: PCNT NM_006031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• microcephalic osteodysplastic primordial dwarfism type II

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCNT	NM_006031.6	c.7024+480C>T		intron_variant	Intron 31 of 46	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6670+480C>T		intron_variant	Intron 31 of 46		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.7024+480C>T		intron_variant	Intron 31 of 46	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27349 AN: 152084 Hom.: 2940 Cov.: 33

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 27352 AN: 152202 Hom.: 2938 Cov.: 33 AF XY: 0.180 AC XY: 13390 AN XY: 74388

African (AFR) AF: 0.0759 AC: 3156 AN: 41556

American (AMR) AF: 0.163 AC: 2486 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3472

East Asian (EAS) AF: 0.420 AC: 2167 AN: 5162

South Asian (SAS) AF: 0.239 AC: 1149 AN: 4802

European-Finnish (FIN) AF: 0.230 AC: 2441 AN: 10602

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14372 AN: 67996

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.179 Hom.: 356

Bravo AF: 0.172

Asia WGS AF: 0.291 AC: 1011 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.48
DANN	Benign	0.44
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2268524; hg19: chr21-47838700;