rs2839228

Variant names:

• chr21-46366902-C-G
• rs2839228
• NM_006031.6:c.2928C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46366902-C-G
• chr21-46366902-C-A

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.2928C>G​(p.Leu976Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,614,110 control chromosomes in the GnomAD database, including 610,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (57590 hom., cov: 35)
  • Exomes 𝑓: 0.87 (552640 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0530
• Publications: 31 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=-0.57).
• BP6: Variant 21-46366902-C-G is Benign according to our data. Variant chr21-46366902-C-G is described in ClinVar as Benign. ClinVar VariationId is 159579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.053 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 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.2928C>G	p.Leu976Leu	synonymous	Exon 15 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.2574C>G	p.Leu858Leu	synonymous	Exon 15 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.2928C>G	p.Leu976Leu	synonymous	Exon 15 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.2574C>G	p.Leu858Leu	synonymous	Exon 15 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.2928C>G	p.Leu976Leu	synonymous	Exon 15 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.869 AC: 132281 AN: 152160 Hom.: 57564 Cov.: 35

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.876

GnomAD2 exomes AF: 0.853 AC: 214275 AN: 251322 AF XY: 0.850

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.887

Gnomad EAS exome AF: 0.816

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.869 AC: 1270024 AN: 1461832 Hom.: 552640 Cov.: 62 AF XY: 0.866 AC XY: 629409 AN XY: 727220

African (AFR) AF: 0.897 AC: 30044 AN: 33480

American (AMR) AF: 0.832 AC: 37228 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23235 AN: 26136

East Asian (EAS) AF: 0.779 AC: 30914 AN: 39700

South Asian (SAS) AF: 0.790 AC: 68139 AN: 86258

European-Finnish (FIN) AF: 0.842 AC: 44947 AN: 53396

Middle Eastern (MID) AF: 0.836 AC: 4819 AN: 5764

European-Non Finnish (NFE) AF: 0.880 AC: 978343 AN: 1111982

Other (OTH) AF: 0.867 AC: 52355 AN: 60394

GnomAD4 genome AF: 0.869 AC: 132360 AN: 152278 Hom.: 57590 Cov.: 35 AF XY: 0.863 AC XY: 64242 AN XY: 74444

African (AFR) AF: 0.896 AC: 37231 AN: 41572

American (AMR) AF: 0.838 AC: 12826 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3039 AN: 3472

East Asian (EAS) AF: 0.807 AC: 4165 AN: 5164

South Asian (SAS) AF: 0.790 AC: 3807 AN: 4822

European-Finnish (FIN) AF: 0.842 AC: 8929 AN: 10606

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59529 AN: 68022

Other (OTH) AF: 0.877 AC: 1853 AN: 2114

Alfa AF: 0.872 Hom.: 18842

Bravo AF: 0.873

Asia WGS AF: 0.797 AC: 2774 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephalic osteodysplastic primordial dwarfism type II (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.6
DANN	Benign	0.43
PhyloP100		0.053
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: rs2839228; hg19: chr21-47786817; COSMIC: COSV64031160;