rs61735810

Positions:

• chr21-46411815-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006031.6(PCNT):​c.5742G>A​(p.Ala1914=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,579,220 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (46 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.48

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-46411815-G-A is Benign according to our data. Variant chr21-46411815-G-A is described in ClinVar as [Benign]. Clinvar id is 159624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46411815-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2199/152338) while in subpopulation AFR AF= 0.0499 (2077/41586). AF 95% confidence interval is 0.0482. There are 45 homozygotes in gnomad4. There are 1005 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.5742G>A	p.Ala1914=	synonymous_variant	28/47	ENST00000359568.10
PCNT	NM_001315529.2	c.5388G>A	p.Ala1796=	synonymous_variant	28/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.5742G>A	p.Ala1914=	synonymous_variant	28/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2193 AN: 152220 Hom.: 44 Cov.: 34

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00378 AC: 713 AN: 188380 Hom.: 14 AF XY: 0.00299 AC XY: 314 AN XY: 105044

Gnomad AFR exome AF: 0.0576

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000451

Gnomad EAS exome AF: 0.000629

Gnomad SAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00149 AC: 2128 AN: 1426882 Hom.: 46 Cov.: 34 AF XY: 0.00129 AC XY: 912 AN XY: 708154

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.000508

Gnomad4 EAS exome AF: 0.000261

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.0144 AC: 2199 AN: 152338 Hom.: 45 Cov.: 34 AF XY: 0.0135 AC XY: 1005 AN XY: 74486

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0169 Hom.: 146

Bravo AF: 0.0166

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.062
DANN	Benign	0.60

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: rs61735810; hg19: chr21-47831729;