rs61735812

Positions:

• chr21-46416657-C-T

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.6739C>T​(p.His2247Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,563,558 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (23 hom., cov: 32)
  • Exomes 𝑓: 0.010 (104 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.182

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025939345).
• BP6: Variant 21-46416657-C-T is Benign according to our data. Variant chr21-46416657-C-T is described in ClinVar as [Benign]. Clinvar id is 138627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46416657-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0151 (2299/152288) while in subpopulation AFR AF= 0.0253 (1050/41568). AF 95% confidence interval is 0.024. There are 23 homozygotes in gnomad4. There are 1149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCNT	NM_006031.6	c.6739C>T	p.His2247Tyr	missense_variant	30/47	ENST00000359568.10	NP_006022.3
PCNT	NM_001315529.2	c.6385C>T	p.His2129Tyr	missense_variant	30/47		NP_001302458.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCNT	ENST00000359568.10	c.6739C>T	p.His2247Tyr	missense_variant	30/47	1	NM_006031.6	ENSP00000352572.5

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2293 AN: 152170 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0118 AC: 2409 AN: 204038 Hom.: 20 AF XY: 0.0118 AC XY: 1291 AN XY: 109462

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.000231

Gnomad SAS exome AF: 0.00663

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.0101 AC: 14198 AN: 1411270 Hom.: 104 Cov.: 34 AF XY: 0.0100 AC XY: 6991 AN XY: 696664

Gnomad4 AFR exome AF: 0.0288

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00557

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.00960

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0151 AC: 2299 AN: 152288 Hom.: 23 Cov.: 32 AF XY: 0.0154 AC XY: 1149 AN XY: 74464

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0212

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0116 Hom.: 17

Bravo AF: 0.0152

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.0203 AC: 89

ESP6500EA AF: 0.0110 AC: 94

ExAC AF: 0.0114 AC: 1374

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2014	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcephalic osteodysplastic primordial dwarfism type II Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.65
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.038
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.78	P
Vest4		0.062
MPC		0.22
ClinPred		0.0022	T
GERP RS		-1.6
Varity_R		0.037
gMVP		0.11

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: rs61735812; hg19: chr21-47836571;