21-46370521-A-G

Variant names:

• chr21-46370521-A-G
• rs2839231
• NM_006031.6:c.3165+3382A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006031.6(PCNT):​c.3165+3382A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 151,838 control chromosomes in the GnomAD database, including 44,736 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44736 hom., cov: 30)
• Consequence: PCNT NM_006031.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.3165+3382A>G		intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.2811+3382A>G		intron	N/A	NP_001302458.1	O95613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.3165+3382A>G		intron	N/A	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.2811+3382A>G		intron	N/A	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.3165+3382A>G		intron	N/A	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.758 AC: 114947 AN: 151720 Hom.: 44679 Cov.: 30

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.712

Gnomad OTH AF: 0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.758 AC: 115060 AN: 151838 Hom.: 44736 Cov.: 30 AF XY: 0.750 AC XY: 55560 AN XY: 74110

African (AFR) AF: 0.928 AC: 38453 AN: 41454

American (AMR) AF: 0.620 AC: 9465 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2771 AN: 3468

East Asian (EAS) AF: 0.656 AC: 3369 AN: 5138

South Asian (SAS) AF: 0.669 AC: 3219 AN: 4812

European-Finnish (FIN) AF: 0.660 AC: 6909 AN: 10476

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.712 AC: 48341 AN: 67914

Other (OTH) AF: 0.760 AC: 1607 AN: 2114

Alfa AF: 0.739 Hom.: 7820

Bravo AF: 0.763

Asia WGS AF: 0.694 AC: 2411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.73
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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: rs2839231; hg19: chr21-47790436;