chr21-46432086-A-C

Variant names:

• chr21-46432086-A-C
• rs774517427
• NM_006031.6:c.8622A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006031.6(PCNT):​c.8622A>C​(p.Glu2874Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E2874E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0400
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05525565).

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.8622A>C	p.Glu2874Asp	missense	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8160+108A>C		intron	N/A	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.8622A>C	p.Glu2874Asp	missense	Exon 38 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.8160+108A>C		intron	N/A	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.8655A>C	p.Glu2885Asp	missense	Exon 39 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2874 of the PCNT protein (p.Glu2874Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PCNT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1477217). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.9
DANN	Benign	0.89
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.040
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.026
Sift	Benign	0.48	T
Sift4G	Benign	0.56	T
Polyphen		0.13	B
Vest4		0.19
MutPred		0.15		Gain of MoRF binding (P = 0.0898)
MVP		0.28
MPC		0.27
ClinPred		0.053	T
GERP RS		-4.3
Varity_R		0.027
gMVP		0.11
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs774517427; hg19: chr21-47852000;