rs139432601

Variant names:

• chr21-46397393-C-G
• rs139432601
• NM_006031.6:c.4345C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.4345C>G​(p.Gln1449Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,208 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (49 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.17
• Publications: 11 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=0.005584389).
• BP6: Variant 21-46397393-C-G is Benign according to our data. Variant chr21-46397393-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00378 (576/152362) while in subpopulation NFE AF = 0.00698 (475/68036). AF 95% confidence interval is 0.00646. There are 5 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.4345C>G	p.Gln1449Glu	missense	Exon 22 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.3991C>G	p.Gln1331Glu	missense	Exon 22 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.4345C>G	p.Gln1449Glu	missense	Exon 22 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.3991C>G	p.Gln1331Glu	missense	Exon 22 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.4378C>G	p.Gln1460Glu	missense	Exon 23 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 576 AN: 152244 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00344 AC: 864 AN: 251342 AF XY: 0.00364

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00610 AC: 8913 AN: 1461846 Hom.: 49 Cov.: 32 AF XY: 0.00590 AC XY: 4288 AN XY: 727218

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86256

European-Finnish (FIN) AF: 0.000862 AC: 46 AN: 53394

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00729 AC: 8103 AN: 1111994

Other (OTH) AF: 0.00669 AC: 404 AN: 60394

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152362 Hom.: 5 Cov.: 33 AF XY: 0.00309 AC XY: 230 AN XY: 74506

African (AFR) AF: 0.00123 AC: 51 AN: 41590

American (AMR) AF: 0.00183 AC: 28 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00698 AC: 475 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00572 Hom.: 4

Bravo AF: 0.00377

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00308 AC: 374

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00569

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Microcephalic osteodysplastic primordial dwarfism type II (4)
-	-	3	not specified (3)
-	-	1	Intellectual disability (1)
-	-	1	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D
Sift4G	Benign	0.26	T
Polyphen		0.69	P
Vest4		0.12
MVP		0.49
MPC		0.14
ClinPred		0.010	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.023
Mutation Taster		=93/7	polymorphism

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: rs139432601; hg19: chr21-47817307; COSMIC: COSV100856262;