chr21-46334635-G-A

Position:

• chr21-46334635-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006031.6(PCNT):​c.506G>A​(p.Arg169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.00300

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04049015).
• BP6: Variant 21-46334635-G-A is Benign according to our data. Variant chr21-46334635-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159616.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}. Variant chr21-46334635-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.506G>A	p.Arg169His	missense_variant	3/47	ENST00000359568.10
PCNT	NM_001315529.2	c.152G>A	p.Arg51His	missense_variant	3/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.506G>A	p.Arg169His	missense_variant	3/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 43 AN: 137968 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000643

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.000416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00107

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000503 AC: 72 AN: 1430710 Hom.: 0 Cov.: 33 AF XY: 0.0000646 AC XY: 46 AN XY: 711552

Gnomad4 AFR exome AF: 0.000186

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.000162

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000311 AC: 43 AN: 138084 Hom.: 0 Cov.: 33 AF XY: 0.000325 AC XY: 22 AN XY: 67626

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000642

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000439

Gnomad4 FIN AF: 0.000416

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00106

Alfa AF: 0.00444 Hom.: 0

ExAC AF: 0.00119 AC: 144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephalic osteodysplastic primordial dwarfism type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2020

This variant is associated with the following publications: (PMID: 29778030) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.91
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.088
Sift	Benign	0.086	T
Sift4G	Benign	0.097	T
Polyphen		0.99	D
Vest4		0.34
MVP		0.34
MPC		0.42
ClinPred		0.028	T
GERP RS		0.23
Varity_R		0.024
gMVP		0.042

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: rs61735823; hg19: chr21-47754549; COSMIC: COSV64026769;