dbSNP rs797045876: PCNT:p.Glu59Lys (chr21-46326497-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006031.6(PCNT):c.175G>A(p.Glu59Lys) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E59E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

PCNT
NM_006031.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0510

Publications

1 publications found

Variant links:

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

PCNT links:

LOC128092249 (HGNC:0):

LOC128092249 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.060687035).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	NM_006031.6	MANE Select	c.175G>A	p.Glu59Lys	missense	Exon 2 of 47	NP_006022.3
PCNT	NM_001315529.2		c.-180G>A		5_prime_UTR	Exon 2 of 47	NP_001302458.1
LOC128092249	NM_001414902.1	MANE Select	c.*6G>A		downstream_gene	N/A	NP_001401831.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCNT	ENST00000359568.10	TSL:1 MANE Select	c.175G>A	p.Glu59Lys	missense	Exon 2 of 47	ENSP00000352572.5
PCNT	ENST00000480896.5	TSL:1	c.-180G>A		5_prime_UTR	Exon 2 of 47	ENSP00000511989.1
PCNT	ENST00000695558.1		c.175G>A	p.Glu59Lys	missense	Exon 2 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.42

M_CAP

Benign

0.010

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.97

PhyloP100

-0.051

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.84

REVEL

Benign

0.018

Sift

Benign

0.25

Sift4G

Benign

0.33

Polyphen

0.0030

Vest4

0.19

MutPred

0.13

Gain of ubiquitination at E59 (P = 0.0016)

MVP

0.33

MPC

0.092

ClinPred

0.072

GERP RS

-3.0

PromoterAI

0.060

Neutral

(source)

Varity_R

0.11

gMVP

0.022

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over