rs536281306

Variant names:

• chr21-46411899-G-A
• rs536281306
• NM_006031.6:c.5826G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006031.6(PCNT):​c.5826G>A​(p.Arg1942Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,581,796 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.336
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• Moyamoya disease

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-46411899-G-A is Benign according to our data. Variant chr21-46411899-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.336 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000302 (46/152346) while in subpopulation EAS AF = 0.00775 (40/5162). AF 95% confidence interval is 0.00585. There are 1 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006031.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.5826G>A	p.Arg1942Arg	synonymous	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5472G>A	p.Arg1824Arg	synonymous	Exon 28 of 47	NP_001302458.1	O95613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.5826G>A	p.Arg1942Arg	synonymous	Exon 28 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.5472G>A	p.Arg1824Arg	synonymous	Exon 28 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.5859G>A	p.Arg1953Arg	synonymous	Exon 29 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152228 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00773

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000482 AC: 94 AN: 195186 AF XY: 0.000542

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00513

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000349

Gnomad OTH exome AF: 0.000584

GnomAD4 exome AF: 0.000410 AC: 586 AN: 1429450 Hom.: 5 Cov.: 34 AF XY: 0.000439 AC XY: 312 AN XY: 710340

African (AFR) AF: 0.00 AC: 0 AN: 33066

American (AMR) AF: 0.0000239 AC: 1 AN: 41802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.0137 AC: 529 AN: 38730

South Asian (SAS) AF: 0.000296 AC: 25 AN: 84360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37846

Middle Eastern (MID) AF: 0.000212 AC: 1 AN: 4714

European-Non Finnish (NFE) AF: 0.00000815 AC: 9 AN: 1103758

Other (OTH) AF: 0.000353 AC: 21 AN: 59442

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152346 Hom.: 1 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00775 AC: 40 AN: 5162

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.000230

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.1
DANN	Benign	0.56
PhyloP100		-0.34
Mutation Taster		=99/1	polymorphism

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: rs536281306; hg19: chr21-47831813;