rs62224222

Positions:

• chr21-46397333-C-T
• chr21-46397333-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.4285C>T​(p.Arg1429Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,613,950 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (40 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.691

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008030057).
• BP6: Variant 21-46397333-C-T is Benign according to our data. Variant chr21-46397333-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46397333-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00405 (617/152202) while in subpopulation NFE AF= 0.00653 (444/68024). AF 95% confidence interval is 0.00603. There are 1 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.4285C>T	p.Arg1429Cys	missense_variant	22/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.3931C>T	p.Arg1311Cys	missense_variant	22/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.4285C>T	p.Arg1429Cys	missense_variant	22/47	1	NM_006031.6	ENSP00000352572	P2
PCNT	ENST00000480896.5	c.3931C>T	p.Arg1311Cys	missense_variant	22/47	1		ENSP00000511989	A2
PCNT	ENST00000695558.1	c.4318C>T	p.Arg1440Cys	missense_variant	23/48			ENSP00000512015	A2
PCNT	ENST00000703224.1	c.*3528C>T		3_prime_UTR_variant, NMD_transcript_variant	24/49			ENSP00000515242

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152084 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00394 AC: 991 AN: 251242 Hom.: 3 AF XY: 0.00395 AC XY: 537 AN XY: 135808

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00654 AC: 9553 AN: 1461748 Hom.: 40 Cov.: 32 AF XY: 0.00632 AC XY: 4594 AN XY: 727186

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00792

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152202 Hom.: 1 Cov.: 33 AF XY: 0.00339 AC XY: 252 AN XY: 74410

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00587 Hom.: 4

Bravo AF: 0.00454

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00373 AC: 453

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00693

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PCNT: BP4, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.93	N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.88	P
Vest4		0.38
MVP		0.65
MPC		0.46
ClinPred		0.015	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.080

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: rs62224222; hg19: chr21-47817247;