rs2839223

Variant names:

• chr21-46357148-G-A
• rs2839223
• NM_006031.6:c.2111G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46357148-G-A
• chr21-46357148-G-C
• chr21-46357148-G-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.2111G>A​(p.Gly704Glu) variant causes a missense change. The variant allele was found at a frequency of 0.871 in 1,613,510 control chromosomes in the GnomAD database, including 613,305 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58889 hom., cov: 33)
  • Exomes 𝑓: 0.87 (554416 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.93
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.448388E-7).
• BP6: Variant 21-46357148-G-A is Benign according to our data. Variant chr21-46357148-G-A is described in ClinVar as Benign. ClinVar VariationId is 159569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.919 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.2111G>A	p.Gly704Glu	missense	Exon 13 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.1757G>A	p.Gly586Glu	missense	Exon 13 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.2111G>A	p.Gly704Glu	missense	Exon 13 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.1757G>A	p.Gly586Glu	missense	Exon 13 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.2111G>A	p.Gly704Glu	missense	Exon 13 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133672 AN: 152134 Hom.: 58844 Cov.: 33

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.882

GnomAD2 exomes AF: 0.855 AC: 214930 AN: 251322 AF XY: 0.852

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.816

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.870 AC: 1271841 AN: 1461258 Hom.: 554416 Cov.: 44 AF XY: 0.867 AC XY: 630286 AN XY: 726996

African (AFR) AF: 0.927 AC: 31017 AN: 33474

American (AMR) AF: 0.834 AC: 37296 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23241 AN: 26132

East Asian (EAS) AF: 0.783 AC: 31078 AN: 39694

South Asian (SAS) AF: 0.791 AC: 68243 AN: 86240

European-Finnish (FIN) AF: 0.842 AC: 44955 AN: 53412

Middle Eastern (MID) AF: 0.839 AC: 4833 AN: 5762

European-Non Finnish (NFE) AF: 0.881 AC: 978634 AN: 1111448

Other (OTH) AF: 0.870 AC: 52544 AN: 60374

GnomAD4 genome AF: 0.879 AC: 133775 AN: 152252 Hom.: 58889 Cov.: 33 AF XY: 0.873 AC XY: 64958 AN XY: 74434

African (AFR) AF: 0.927 AC: 38520 AN: 41566

American (AMR) AF: 0.842 AC: 12883 AN: 15294

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

East Asian (EAS) AF: 0.808 AC: 4175 AN: 5170

South Asian (SAS) AF: 0.791 AC: 3820 AN: 4828

European-Finnish (FIN) AF: 0.842 AC: 8929 AN: 10610

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59562 AN: 67996

Other (OTH) AF: 0.883 AC: 1864 AN: 2112

Alfa AF: 0.878 Hom.: 130998

Bravo AF: 0.883

TwinsUK AF: 0.878 AC: 3257

ALSPAC AF: 0.883 AC: 3402

ESP6500AA AF: 0.929 AC: 4094

ESP6500EA AF: 0.876 AC: 7531

ExAC AF: 0.856 AC: 103914

Asia WGS AF: 0.806 AC: 2806 AN: 3478

EpiCase AF: 0.874

EpiControl AF: 0.875

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.15
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.4	N
PhyloP100		3.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.060
MPC		0.10
ClinPred		0.0018	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.014
Mutation Taster		=99/1	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: rs2839223; hg19: chr21-47777063; COSMIC: COSV64030971; COSMIC: COSV64030971;