21-46324213-G-T

Variant names:

• chr21-46324213-G-T
• rs138595914
• NM_006031.6:c.-16G>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.135
• Publications: 8 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 -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.
• 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 rank	MANE	Protein	UniProt
PCNT	NM_006031.6	c.-16G>T		5_prime_UTR_variant	Exon 1 of 47	ENST00000359568.10	NP_006022.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.-16G>T		5_prime_UTR_variant	Exon 1 of 47	1	NM_006031.6	ENSP00000352572.5

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

GnomAD2 exomes AF: 0.0440 AC: 10480 AN: 238208 AF XY: 0.0439

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 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

African (AFR) AF: 0.00824 AC: 275 AN: 33386

American (AMR) AF: 0.0203 AC: 892 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1430 AN: 25918

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39534

South Asian (SAS) AF: 0.0135 AC: 1149 AN: 85304

European-Finnish (FIN) AF: 0.0853 AC: 4497 AN: 52718

Middle Eastern (MID) AF: 0.0249 AC: 143 AN: 5746

European-Non Finnish (NFE) AF: 0.0642 AC: 71174 AN: 1108022

Other (OTH) AF: 0.0500 AC: 3005 AN: 60056

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

African (AFR) AF: 0.0101 AC: 419 AN: 41576

American (AMR) AF: 0.0262 AC: 401 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0562 AC: 195 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0858 AC: 910 AN: 10612

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0661 AC: 4493 AN: 68008

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0356 Hom.: 47

Bravo AF: 0.0375

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 31, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.14
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=296/4	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: rs138595914; hg19: chr21-47744127; COSMIC: COSV52449400; COSMIC: COSV52449400;