rs587784304

chr21-46391335-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006031.6(PCNT):c.4175G>A(p.Arg1392Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,556,868 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R1392W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.41

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041094124).
• BP6: Variant 21-46391335-G-A is Benign according to our data. Variant chr21-46391335-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159596.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr21-46391335-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.4175G>A	p.Arg1392Gln	missense_variant	21/47	ENST00000359568.10
PCNT	NM_001315529.2	c.3821G>A	p.Arg1274Gln	missense_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.4175G>A	p.Arg1392Gln	missense_variant	21/47	1	NM_006031.6	P2
PCNT	ENST00000480896.5	c.3821G>A	p.Arg1274Gln	missense_variant	21/47	1		A2
PCNT	ENST00000695558.1	c.4175G>A	p.Arg1392Gln	missense_variant	21/48			A2
PCNT	ENST00000703224.1	c.*3418G>A		3_prime_UTR_variant, NMD_transcript_variant	23/49

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000545 AC: 86 AN: 157768 Hom.: 2 AF XY: 0.000773 AC XY: 65 AN XY: 84136

Gnomad AFR exome AF: 0.000116

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00362

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000184 AC: 258 AN: 1404600 Hom.: 2 Cov.: 32 AF XY: 0.000287 AC XY: 199 AN XY: 693394

Gnomad4 AFR exome AF: 0.0000623

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000554

Gnomad4 OTH exome AF: 0.000223

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.000474 AC: 53

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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

Nov 13, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.75
Dann	Benign	0.35
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.7	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.079
MutPred		0.11		Loss of MoRF binding (P = 0.014);
MVP		0.31
MPC		0.093
ClinPred		0.0085	T
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.012
gMVP		0.018

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: rs587784304; hg19: chr21-47811250;