NM_006031.6:c.7130C>T

Variant names:

• chr21-46422075-C-T
• rs61735814
• NM_006031.6:c.7130C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.7130C>T​(p.Pro2377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,866 control chromosomes in the GnomAD database, including 2,622 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2377P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (195 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2427 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.50
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017070472).
• BP6: Variant 21-46422075-C-T is Benign according to our data. Variant chr21-46422075-C-T is described in ClinVar as Benign. ClinVar VariationId is 138631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.7130C>T	p.Pro2377Leu	missense	Exon 32 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6776C>T	p.Pro2259Leu	missense	Exon 32 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.7130C>T	p.Pro2377Leu	missense	Exon 32 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.6776C>T	p.Pro2259Leu	missense	Exon 32 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.7163C>T	p.Pro2388Leu	missense	Exon 33 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6311 AN: 152194 Hom.: 196 Cov.: 33

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0625

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0431 AC: 10807 AN: 251014 AF XY: 0.0430

Gnomad AFR exome AF: 0.00857

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0570

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0864

Gnomad NFE exome AF: 0.0608

Gnomad OTH exome AF: 0.0464

GnomAD4 exome AF: 0.0538 AC: 78595 AN: 1461554 Hom.: 2427 Cov.: 32 AF XY: 0.0528 AC XY: 38378 AN XY: 727076

African (AFR) AF: 0.00777 AC: 260 AN: 33480

American (AMR) AF: 0.0198 AC: 884 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 1447 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0135 AC: 1168 AN: 86258

European-Finnish (FIN) AF: 0.0834 AC: 4436 AN: 53160

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5768

European-Non Finnish (NFE) AF: 0.0606 AC: 67396 AN: 1111940

Other (OTH) AF: 0.0473 AC: 2858 AN: 60390

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152312 Hom.: 195 Cov.: 33 AF XY: 0.0408 AC XY: 3042 AN XY: 74468

African (AFR) AF: 0.00979 AC: 407 AN: 41586

American (AMR) AF: 0.0261 AC: 399 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.0851 AC: 903 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4250 AN: 68016

Other (OTH) AF: 0.0378 AC: 80 AN: 2116

Alfa AF: 0.0501 Hom.: 391

Bravo AF: 0.0360

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0609 AC: 524

ExAC AF: 0.0433 AC: 5263

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0541

EpiControl AF: 0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 31, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Microcephalic osteodysplastic primordial dwarfism type II Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.085
DANN	Benign	0.63
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.086
Sift	Benign	0.23	T
Sift4G	Benign	0.13	T
Polyphen		0.76	P
Vest4		0.031
MPC		0.41
ClinPred		0.012	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.011
gMVP		0.094
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61735814; hg19: chr21-47841989; COSMIC: COSV64027462; COSMIC: COSV64027462;