NM_006031.6:c.6384A>G

Variant names:

• chr21-46416302-A-G
• rs60444527
• NM_006031.6:c.6384A>G

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.6384A>G​(p.Thr2128Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 1,613,756 control chromosomes in the GnomAD database, including 12,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4358 hom., cov: 32)
  • Exomes 𝑓: 0.082 (7719 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.488
• Publications: 8 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=-0.91).
• BP6: Variant 21-46416302-A-G is Benign according to our data. Variant chr21-46416302-A-G is described in ClinVar as Benign. ClinVar VariationId is 138623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.488 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 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.6384A>G	p.Thr2128Thr	synonymous	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6030A>G	p.Thr2010Thr	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.6384A>G	p.Thr2128Thr	synonymous	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6030A>G	p.Thr2010Thr	synonymous	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6417A>G	p.Thr2139Thr	synonymous	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26807 AN: 151920 Hom.: 4353 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0916

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.0958 AC: 24075 AN: 251426 AF XY: 0.0904

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.0863

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.0823

GnomAD4 exome AF: 0.0817 AC: 119430 AN: 1461718 Hom.: 7719 Cov.: 34 AF XY: 0.0808 AC XY: 58786 AN XY: 727172

African (AFR) AF: 0.456 AC: 15279 AN: 33474

American (AMR) AF: 0.0597 AC: 2671 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 2218 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39700

South Asian (SAS) AF: 0.0849 AC: 7319 AN: 86254

European-Finnish (FIN) AF: 0.103 AC: 5525 AN: 53416

Middle Eastern (MID) AF: 0.0739 AC: 426 AN: 5768

European-Non Finnish (NFE) AF: 0.0720 AC: 80044 AN: 1111868

Other (OTH) AF: 0.0974 AC: 5881 AN: 60378

GnomAD4 genome AF: 0.177 AC: 26845 AN: 152038 Hom.: 4358 Cov.: 32 AF XY: 0.173 AC XY: 12869 AN XY: 74326

African (AFR) AF: 0.433 AC: 17933 AN: 41378

American (AMR) AF: 0.0937 AC: 1433 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 300 AN: 3468

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5184

South Asian (SAS) AF: 0.0914 AC: 440 AN: 4812

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0762 AC: 5180 AN: 67988

Other (OTH) AF: 0.166 AC: 350 AN: 2112

Alfa AF: 0.122 Hom.: 1288

Bravo AF: 0.187

Asia WGS AF: 0.103 AC: 357 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0705

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.30
PhyloP100		-0.49
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: rs60444527; hg19: chr21-47836216; COSMIC: COSV64029125; COSMIC: COSV64029125;