rs2073376

Variant names:

• chr21-46431839-A-G
• rs2073376
• NM_006031.6:c.8375A>G

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.8375A>G​(p.Gln2792Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,546 control chromosomes in the GnomAD database, including 322,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34980 hom., cov: 34)
  • Exomes 𝑓: 0.63 (287790 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0810
• Publications: 52 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=6.886558E-7).
• BP6: Variant 21-46431839-A-G is Benign according to our data. Variant chr21-46431839-A-G is described in ClinVar as Benign. ClinVar VariationId is 159671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 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.8375A>G	p.Gln2792Arg	missense	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8021A>G	p.Gln2674Arg	missense	Exon 38 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.8375A>G	p.Gln2792Arg	missense	Exon 38 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.8021A>G	p.Gln2674Arg	missense	Exon 38 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.8408A>G	p.Gln2803Arg	missense	Exon 39 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102083 AN: 152028 Hom.: 34935 Cov.: 34

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.695

GnomAD2 exomes AF: 0.627 AC: 156951 AN: 250436 AF XY: 0.629

Gnomad AFR exome AF: 0.794

Gnomad AMR exome AF: 0.483

Gnomad ASJ exome AF: 0.735

Gnomad EAS exome AF: 0.633

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.639

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.625 AC: 913994 AN: 1461402 Hom.: 287790 Cov.: 71 AF XY: 0.627 AC XY: 455793 AN XY: 727008

African (AFR) AF: 0.804 AC: 26918 AN: 33480

American (AMR) AF: 0.495 AC: 22144 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 19218 AN: 26134

East Asian (EAS) AF: 0.674 AC: 26738 AN: 39700

South Asian (SAS) AF: 0.621 AC: 53584 AN: 86244

European-Finnish (FIN) AF: 0.617 AC: 32710 AN: 53056

Middle Eastern (MID) AF: 0.730 AC: 4212 AN: 5766

European-Non Finnish (NFE) AF: 0.620 AC: 689795 AN: 1111934

Other (OTH) AF: 0.640 AC: 38675 AN: 60392

GnomAD4 genome AF: 0.672 AC: 102180 AN: 152144 Hom.: 34980 Cov.: 34 AF XY: 0.666 AC XY: 49559 AN XY: 74368

African (AFR) AF: 0.791 AC: 32841 AN: 41538

American (AMR) AF: 0.576 AC: 8806 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2579 AN: 3470

East Asian (EAS) AF: 0.639 AC: 3303 AN: 5170

South Asian (SAS) AF: 0.626 AC: 3022 AN: 4828

European-Finnish (FIN) AF: 0.606 AC: 6398 AN: 10552

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42891 AN: 67984

Other (OTH) AF: 0.696 AC: 1471 AN: 2112

Alfa AF: 0.644 Hom.: 117146

Bravo AF: 0.675

TwinsUK AF: 0.616 AC: 2284

ALSPAC AF: 0.617 AC: 2376

ESP6500AA AF: 0.792 AC: 3491

ESP6500EA AF: 0.640 AC: 5507

ExAC AF: 0.639 AC: 77537

Asia WGS AF: 0.679 AC: 2360 AN: 3478

EpiCase AF: 0.635

EpiControl AF: 0.645

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)
-	-	1	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.11
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.081
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.087
ClinPred		0.0013	T
GERP RS		2.3
Varity_R		0.016
gMVP		0.023
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: rs2073376; hg19: chr21-47851753; COSMIC: COSV64028610;