rs2839227

Variant names:

• chr21-46366609-A-G
• rs2839227
• NM_006031.6:c.2635A>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.2635A>G​(p.Thr879Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,858 control chromosomes in the GnomAD database, including 29,428 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T879T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (7074 hom., cov: 33)
  • Exomes 𝑓: 0.16 (22354 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.77
• Publications: 54 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=7.278025E-4).
• BP6: Variant 21-46366609-A-G is Benign according to our data. Variant chr21-46366609-A-G is described in ClinVar as Benign. ClinVar VariationId is 159575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.2635A>G	p.Thr879Ala	missense	Exon 15 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.2281A>G	p.Thr761Ala	missense	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.2635A>G	p.Thr879Ala	missense	Exon 15 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.2281A>G	p.Thr761Ala	missense	Exon 15 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.2635A>G	p.Thr879Ala	missense	Exon 15 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39424 AN: 152004 Hom.: 7049 Cov.: 33

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.197 AC: 49393 AN: 250338 AF XY: 0.196

Gnomad AFR exome AF: 0.518

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.158 AC: 230292 AN: 1461736 Hom.: 22354 Cov.: 63 AF XY: 0.161 AC XY: 117162 AN XY: 727176

African (AFR) AF: 0.532 AC: 17820 AN: 33478

American (AMR) AF: 0.204 AC: 9101 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3277 AN: 26136

East Asian (EAS) AF: 0.223 AC: 8865 AN: 39700

South Asian (SAS) AF: 0.282 AC: 24360 AN: 86256

European-Finnish (FIN) AF: 0.178 AC: 9518 AN: 53350

Middle Eastern (MID) AF: 0.208 AC: 1197 AN: 5768

European-Non Finnish (NFE) AF: 0.131 AC: 145340 AN: 1111932

Other (OTH) AF: 0.179 AC: 10814 AN: 60394

GnomAD4 genome AF: 0.260 AC: 39503 AN: 152122 Hom.: 7074 Cov.: 33 AF XY: 0.263 AC XY: 19564 AN XY: 74360

African (AFR) AF: 0.510 AC: 21171 AN: 41476

American (AMR) AF: 0.223 AC: 3417 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1023 AN: 5146

South Asian (SAS) AF: 0.294 AC: 1413 AN: 4808

European-Finnish (FIN) AF: 0.181 AC: 1919 AN: 10604

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9322 AN: 68006

Other (OTH) AF: 0.240 AC: 507 AN: 2112

Alfa AF: 0.176 Hom.: 12176

Bravo AF: 0.270

TwinsUK AF: 0.132 AC: 491

ALSPAC AF: 0.129 AC: 497

ESP6500AA AF: 0.501 AC: 2199

ESP6500EA AF: 0.136 AC: 1168

ExAC AF: 0.204 AC: 24797

Asia WGS AF: 0.296 AC: 1027 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.00073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.047
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.17	B
Vest4		0.10
MPC		0.28
ClinPred		0.012	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.046
Mutation Taster		=98/2	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: rs2839227; hg19: chr21-47786524; COSMIC: COSV64026404;