21-46431882-G-A

Variant names:

• chr21-46431882-G-A
• rs9983522
• NM_006031.6:c.8418G>A

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.8418G>A​(p.Ala2806Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,908 control chromosomes in the GnomAD database, including 13,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2806A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1178 hom., cov: 34)
  • Exomes 𝑓: 0.13 (12653 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.49
• Publications: 19 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=-0.85).
• BP6: Variant 21-46431882-G-A is Benign according to our data. Variant chr21-46431882-G-A is described in ClinVar as Benign. ClinVar VariationId is 159673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.19 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.8418G>A	p.Ala2806Ala	synonymous	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8064G>A	p.Ala2688Ala	synonymous	Exon 38 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.8418G>A	p.Ala2806Ala	synonymous	Exon 38 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.8064G>A	p.Ala2688Ala	synonymous	Exon 38 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.8451G>A	p.Ala2817Ala	synonymous	Exon 39 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17958 AN: 152150 Hom.: 1179 Cov.: 34

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.141 AC: 35501 AN: 250904 AF XY: 0.145

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.189

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.126 AC: 184748 AN: 1461640 Hom.: 12653 Cov.: 40 AF XY: 0.130 AC XY: 94283 AN XY: 727118

African (AFR) AF: 0.0660 AC: 2210 AN: 33480

American (AMR) AF: 0.159 AC: 7129 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2883 AN: 26136

East Asian (EAS) AF: 0.221 AC: 8787 AN: 39700

South Asian (SAS) AF: 0.203 AC: 17475 AN: 86254

European-Finnish (FIN) AF: 0.156 AC: 8306 AN: 53226

Middle Eastern (MID) AF: 0.162 AC: 936 AN: 5768

European-Non Finnish (NFE) AF: 0.116 AC: 129398 AN: 1111970

Other (OTH) AF: 0.126 AC: 7624 AN: 60392

GnomAD4 genome AF: 0.118 AC: 17978 AN: 152268 Hom.: 1178 Cov.: 34 AF XY: 0.124 AC XY: 9222 AN XY: 74442

African (AFR) AF: 0.0660 AC: 2743 AN: 41574

American (AMR) AF: 0.156 AC: 2392 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1033 AN: 5172

South Asian (SAS) AF: 0.198 AC: 955 AN: 4826

European-Finnish (FIN) AF: 0.157 AC: 1660 AN: 10596

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8297 AN: 68008

Other (OTH) AF: 0.115 AC: 244 AN: 2116

Alfa AF: 0.121 Hom.: 989

Bravo AF: 0.114

Asia WGS AF: 0.202 AC: 701 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.41
PhyloP100		-2.5
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: rs9983522; hg19: chr21-47851796; COSMIC: COSV64029370;