21-46399774-A-G

Position:

• chr21-46399774-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006031.6(PCNT):​c.4769A>G​(p.Asn1590Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061246425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.4769A>G	p.Asn1590Ser	missense_variant	25/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.4415A>G	p.Asn1472Ser	missense_variant	25/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.4769A>G	p.Asn1590Ser	missense_variant	25/47	1	NM_006031.6	ENSP00000352572	P2
PCNT	ENST00000480896.5	c.4415A>G	p.Asn1472Ser	missense_variant	25/47	1		ENSP00000511989	A2
PCNT	ENST00000695558.1	c.4802A>G	p.Asn1601Ser	missense_variant	26/48			ENSP00000512015	A2
PCNT	ENST00000703224.1	c.*4012A>G		3_prime_UTR_variant, NMD_transcript_variant	27/49			ENSP00000515242

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 12, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.6
DANN	Benign	0.78
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.035
Sift	Benign	0.067	T
Sift4G	Benign	0.29	T
Polyphen		0.49	P
Vest4		0.092
MutPred		0.18		Gain of phosphorylation at N1590 (P = 0.0313);
MVP		0.40
MPC		0.25
ClinPred		0.090	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.032

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784307; hg19: chr21-47819688;