21-46411704-C-T

Variant names:

• chr21-46411704-C-T
• rs16979162
• NM_006031.6:c.5631C>T

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.5631C>T​(p.Ile1877Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0903 in 1,612,646 control chromosomes in the GnomAD database, including 12,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4419 hom., cov: 34)
  • Exomes 𝑓: 0.081 (7630 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.18
• Publications: 12 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 21-46411704-C-T is Benign according to our data. Variant chr21-46411704-C-T is described in ClinVar as Benign. ClinVar VariationId is 95337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.5631C>T	p.Ile1877Ile	synonymous	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5277C>T	p.Ile1759Ile	synonymous	Exon 28 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.5631C>T	p.Ile1877Ile	synonymous	Exon 28 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.5277C>T	p.Ile1759Ile	synonymous	Exon 28 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.5664C>T	p.Ile1888Ile	synonymous	Exon 29 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26931 AN: 152134 Hom.: 4414 Cov.: 34

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0923

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0755

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.0949 AC: 23131 AN: 243784 AF XY: 0.0902

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.00307

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0741

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0812 AC: 118621 AN: 1460394 Hom.: 7630 Cov.: 34 AF XY: 0.0804 AC XY: 58388 AN XY: 726542

African (AFR) AF: 0.456 AC: 15267 AN: 33470

American (AMR) AF: 0.0589 AC: 2635 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 2217 AN: 26122

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39692

South Asian (SAS) AF: 0.0848 AC: 7315 AN: 86256

European-Finnish (FIN) AF: 0.103 AC: 5392 AN: 52178

Middle Eastern (MID) AF: 0.0733 AC: 423 AN: 5768

European-Non Finnish (NFE) AF: 0.0715 AC: 79471 AN: 1111826

Other (OTH) AF: 0.0966 AC: 5834 AN: 60366

GnomAD4 genome AF: 0.177 AC: 26970 AN: 152252 Hom.: 4419 Cov.: 34 AF XY: 0.174 AC XY: 12970 AN XY: 74456

African (AFR) AF: 0.436 AC: 18095 AN: 41530

American (AMR) AF: 0.0937 AC: 1435 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5186

South Asian (SAS) AF: 0.0922 AC: 445 AN: 4828

European-Finnish (FIN) AF: 0.107 AC: 1133 AN: 10610

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5130 AN: 67996

Other (OTH) AF: 0.166 AC: 351 AN: 2114

Alfa AF: 0.110 Hom.: 1293

Bravo AF: 0.187

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.0694

EpiControl AF: 0.0699

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.24
DANN	Benign	0.53
PhyloP100		-3.2
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: rs16979162; hg19: chr21-47831618; COSMIC: COSV64025033;