rs57108405

Variant names:

• chr21-46416512-T-C
• rs57108405
• NM_006031.6:c.6594T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.6594T>C​(p.Gly2198Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,613,746 control chromosomes in the GnomAD database, including 7,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3587 hom., cov: 32)
  • Exomes 𝑓: 0.027 (3744 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.35
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46416512-T-C is Benign according to our data. Variant chr21-46416512-T-C is described in ClinVar as Benign. ClinVar VariationId is 138625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 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.6594T>C	p.Gly2198Gly	synonymous	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6240T>C	p.Gly2080Gly	synonymous	Exon 30 of 47	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.6594T>C	p.Gly2198Gly	synonymous	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6240T>C	p.Gly2080Gly	synonymous	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6627T>C	p.Gly2209Gly	synonymous	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19700 AN: 152114 Hom.: 3583 Cov.: 32

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.0496 AC: 12447 AN: 250708 AF XY: 0.0452

Gnomad AFR exome AF: 0.420

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0265 AC: 38799 AN: 1461514 Hom.: 3744 Cov.: 34 AF XY: 0.0268 AC XY: 19469 AN XY: 727074

African (AFR) AF: 0.433 AC: 14501 AN: 33480

American (AMR) AF: 0.0358 AC: 1602 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 359 AN: 26136

East Asian (EAS) AF: 0.00161 AC: 64 AN: 39700

South Asian (SAS) AF: 0.0726 AC: 6265 AN: 86256

European-Finnish (FIN) AF: 0.0199 AC: 1055 AN: 53070

Middle Eastern (MID) AF: 0.0414 AC: 239 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11915 AN: 1111990

Other (OTH) AF: 0.0463 AC: 2799 AN: 60392

GnomAD4 genome AF: 0.130 AC: 19740 AN: 152232 Hom.: 3587 Cov.: 32 AF XY: 0.127 AC XY: 9441 AN XY: 74412

African (AFR) AF: 0.409 AC: 16975 AN: 41506

American (AMR) AF: 0.0605 AC: 926 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5180

South Asian (SAS) AF: 0.0851 AC: 411 AN: 4832

European-Finnish (FIN) AF: 0.0219 AC: 233 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 847 AN: 68006

Other (OTH) AF: 0.117 AC: 248 AN: 2114

Alfa AF: 0.0602 Hom.: 780

Bravo AF: 0.144

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0151

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.092
DANN	Benign	0.35
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs57108405; hg19: chr21-47836426;