rs529457692

chr21-46355515-G-Achr21-46355515-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006031.6(PCNT):c.1825G>A(p.Glu609Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E609Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0900

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027133852).
• BP6: Variant 21-46355515-G-A is Benign according to our data. Variant chr21-46355515-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3210358.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-46355515-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCNT	NM_006031.6	c.1825G>A	p.Glu609Lys	missense_variant	12/47	ENST00000359568.10
PCNT	NM_001315529.2	c.1471G>A	p.Glu491Lys	missense_variant	12/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCNT	ENST00000359568.10	c.1825G>A	p.Glu609Lys	missense_variant	12/47	1	NM_006031.6	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.20
Dann	Benign	0.88
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.35	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.0070
Sift	Benign	0.90	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.085
MutPred		0.13		Gain of ubiquitination at E609 (P = 0.0045);
MVP		0.18
MPC		0.30
ClinPred		0.039	T
GERP RS		-3.5
Varity_R		0.016
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: rs529457692; hg19: chr21-47775430;