rs2839246

Variant names:

• chr21-46418209-A-G
• rs2839246
• NM_006031.6:c.6927A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.6927A>G​(p.Lys2309Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 1,570,046 control chromosomes in the GnomAD database, including 11,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4400 hom., cov: 33)
  • Exomes 𝑓: 0.078 (7029 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.524
• Publications: 14 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=-0.59).
• BP6: Variant 21-46418209-A-G is Benign according to our data. Variant chr21-46418209-A-G is described in ClinVar as Benign. ClinVar VariationId is 138628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.524 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 is higher than 0.05.

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.6927A>G	p.Lys2309Lys	synonymous	Exon 31 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6573A>G	p.Lys2191Lys	synonymous	Exon 31 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.6927A>G	p.Lys2309Lys	synonymous	Exon 31 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6573A>G	p.Lys2191Lys	synonymous	Exon 31 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6960A>G	p.Lys2320Lys	synonymous	Exon 32 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26886 AN: 152090 Hom.: 4395 Cov.: 33

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.0940 AC: 23543 AN: 250346 AF XY: 0.0889

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0851

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0807

GnomAD4 exome AF: 0.0784 AC: 111215 AN: 1417838 Hom.: 7029 Cov.: 27 AF XY: 0.0780 AC XY: 55273 AN XY: 708320

African (AFR) AF: 0.446 AC: 14126 AN: 31656

American (AMR) AF: 0.0592 AC: 2640 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 2140 AN: 25792

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39540

South Asian (SAS) AF: 0.0834 AC: 7113 AN: 85308

European-Finnish (FIN) AF: 0.103 AC: 5510 AN: 53376

Middle Eastern (MID) AF: 0.0721 AC: 411 AN: 5698

European-Non Finnish (NFE) AF: 0.0686 AC: 73645 AN: 1073110

Other (OTH) AF: 0.0947 AC: 5565 AN: 58740

GnomAD4 genome AF: 0.177 AC: 26924 AN: 152208 Hom.: 4400 Cov.: 33 AF XY: 0.174 AC XY: 12924 AN XY: 74434

African (AFR) AF: 0.434 AC: 17995 AN: 41470

American (AMR) AF: 0.0938 AC: 1434 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 300 AN: 3472

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5186

South Asian (SAS) AF: 0.0916 AC: 442 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10616

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0762 AC: 5184 AN: 68024

Other (OTH) AF: 0.166 AC: 351 AN: 2114

Alfa AF: 0.112 Hom.: 4792

Bravo AF: 0.187

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0692

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.3
DANN	Benign	0.68
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2839246; hg19: chr21-47838123;