21-46431722-G-T

Variant names:

• chr21-46431722-G-T
• rs743346
• NM_006031.6:c.8258G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006031.6(PCNT):​c.8258G>T​(p.Arg2753Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2753H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.465
• Publications: 20 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.327171).

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.8258G>T	p.Arg2753Leu	missense	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7904G>T	p.Arg2635Leu	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.8258G>T	p.Arg2753Leu	missense	Exon 38 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.7904G>T	p.Arg2635Leu	missense	Exon 38 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.8291G>T	p.Arg2764Leu	missense	Exon 39 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 300

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.47
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.031
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.17		Loss of phosphorylation at T2754 (P = 0.091)
MVP		0.51
MPC		0.36
ClinPred		0.97	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.35
Mutation Taster		=94/6	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: rs743346; hg19: chr21-47851636;