chr21-46391357-C-T

Variant names:

• chr21-46391357-C-T
• rs3737438
• NM_006031.6:c.4197C>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.4197C>T​(p.Asp1399Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,550,058 control chromosomes in the GnomAD database, including 105,254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8443 hom., cov: 33)
  • Exomes 𝑓: 0.37 (96811 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.50
• Publications: 17 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=-0.83).
• BP6: Variant 21-46391357-C-T is Benign according to our data. Variant chr21-46391357-C-T is described in ClinVar as Benign. ClinVar VariationId is 159597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 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.4197C>T	p.Asp1399Asp	synonymous	Exon 21 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.3843C>T	p.Asp1281Asp	synonymous	Exon 21 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.4197C>T	p.Asp1399Asp	synonymous	Exon 21 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.3843C>T	p.Asp1281Asp	synonymous	Exon 21 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.4197C>T	p.Asp1399Asp	synonymous	Exon 21 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49013 AN: 151970 Hom.: 8445 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.338 AC: 51576 AN: 152382 AF XY: 0.343

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.386

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.369 AC: 516293 AN: 1397970 Hom.: 96811 Cov.: 41 AF XY: 0.368 AC XY: 254034 AN XY: 689500

African (AFR) AF: 0.214 AC: 6789 AN: 31758

American (AMR) AF: 0.245 AC: 8768 AN: 35750

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 9823 AN: 25152

East Asian (EAS) AF: 0.437 AC: 15738 AN: 35976

South Asian (SAS) AF: 0.307 AC: 24330 AN: 79246

European-Finnish (FIN) AF: 0.342 AC: 16800 AN: 49138

Middle Eastern (MID) AF: 0.411 AC: 1843 AN: 4482

European-Non Finnish (NFE) AF: 0.381 AC: 411417 AN: 1078586

Other (OTH) AF: 0.359 AC: 20785 AN: 57882

GnomAD4 genome AF: 0.322 AC: 49018 AN: 152088 Hom.: 8443 Cov.: 33 AF XY: 0.317 AC XY: 23549 AN XY: 74338

African (AFR) AF: 0.218 AC: 9039 AN: 41490

American (AMR) AF: 0.281 AC: 4301 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3472

East Asian (EAS) AF: 0.411 AC: 2121 AN: 5156

South Asian (SAS) AF: 0.303 AC: 1458 AN: 4816

European-Finnish (FIN) AF: 0.332 AC: 3515 AN: 10582

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25983 AN: 67964

Other (OTH) AF: 0.357 AC: 754 AN: 2112

Alfa AF: 0.353 Hom.: 7528

Bravo AF: 0.317

Asia WGS AF: 0.331 AC: 1153 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.52
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs3737438; hg19: chr21-47811272; COSMIC: COSV64025595;