21-46346953-G-A

Variant names:

• chr21-46346953-G-A
• rs140196457
• NM_006031.6:c.931G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006031.6(PCNT):​c.931G>A​(p.Ala311Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,596,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A311S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 6 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057430714).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.931G>A	p.Ala311Thr	missense	Exon 5 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.577G>A	p.Ala193Thr	missense	Exon 5 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.931G>A	p.Ala311Thr	missense	Exon 5 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.577G>A	p.Ala193Thr	missense	Exon 5 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.931G>A	p.Ala311Thr	missense	Exon 5 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1444694 Hom.: 0 Cov.: 34 AF XY: 0.00000698 AC XY: 5 AN XY: 716836

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 40864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 83116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1105874

Other (OTH) AF: 0.00 AC: 0 AN: 59812

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74392

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Uncertain:1

Jun 16, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.077
Sift	Benign	0.14	T
Sift4G	Benign	0.16	T
Polyphen		0.29	B
Vest4		0.29
MutPred		0.19		Gain of phosphorylation at A311 (P = 0.0199)
MVP		0.33
MPC		0.11
ClinPred		0.18	T
GERP RS		0.17
Varity_R		0.039
gMVP		0.049
Mutation Taster		=96/4	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: rs140196457; hg19: chr21-47766867; COSMIC: COSV64027186; COSMIC: COSV64027186;