rs2839260

Variant names:

• chr21-46440851-T-C
• rs2839260
• NM_006031.6:c.9394-4T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006031.6(PCNT):​c.9394-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,579,672 control chromosomes in the GnomAD database, including 19,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1659 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18037 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002942
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0740
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-46440851-T-C is Benign according to our data. Variant chr21-46440851-T-C is described in ClinVar as Benign. ClinVar VariationId is 159692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 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.9394-4T>C		splice_region intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.8803-4T>C		splice_region intron	N/A	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.9394-4T>C		splice_region intron	N/A	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.8803-4T>C		splice_region intron	N/A	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.9427-4T>C		splice_region intron	N/A	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21325 AN: 152140 Hom.: 1661 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.0947

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.124 AC: 31086 AN: 250258 AF XY: 0.125

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0745

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0156

Gnomad FIN exome AF: 0.0953

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.154 AC: 219537 AN: 1427414 Hom.: 18037 Cov.: 27 AF XY: 0.152 AC XY: 108087 AN XY: 712516

African (AFR) AF: 0.139 AC: 4566 AN: 32760

American (AMR) AF: 0.0789 AC: 3523 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4174 AN: 25906

East Asian (EAS) AF: 0.0130 AC: 514 AN: 39542

South Asian (SAS) AF: 0.0880 AC: 7529 AN: 85532

European-Finnish (FIN) AF: 0.100 AC: 5341 AN: 53294

Middle Eastern (MID) AF: 0.135 AC: 768 AN: 5692

European-Non Finnish (NFE) AF: 0.171 AC: 184755 AN: 1080822

Other (OTH) AF: 0.141 AC: 8367 AN: 59188

GnomAD4 genome AF: 0.140 AC: 21326 AN: 152258 Hom.: 1659 Cov.: 33 AF XY: 0.134 AC XY: 9985 AN XY: 74446

African (AFR) AF: 0.139 AC: 5761 AN: 41538

American (AMR) AF: 0.116 AC: 1768 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.0104 AC: 54 AN: 5188

South Asian (SAS) AF: 0.0813 AC: 392 AN: 4824

European-Finnish (FIN) AF: 0.0947 AC: 1005 AN: 10610

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11321 AN: 68012

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.160 Hom.: 2953

Bravo AF: 0.142

Asia WGS AF: 0.0590 AC: 206 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.174

ClinVar

ClinVar submissions as Germline

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.67
PhyloP100		0.074
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.012
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: rs2839260; hg19: chr21-47860764;