rs2839226

Variant names:

• chr21-46366579-C-T
• rs2839226
• NM_006031.6:c.2610-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-46366579-C-T
• chr21-46366579-C-A
• chr21-46366579-C-G

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.2610-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 1,612,214 control chromosomes in the GnomAD database, including 494,416 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 0.69 (37953 hom., cov: 33)
  • Exomes 𝑓: 0.79 (456463 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.361
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-46366579-C-T is Benign according to our data. Variant chr21-46366579-C-T is described in ClinVar as Benign. ClinVar VariationId is 159574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.795 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.2610-5C>T		splice_region intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.2256-5C>T		splice_region intron	N/A	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.2610-5C>T		splice_region intron	N/A	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.2256-5C>T		splice_region intron	N/A	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.2610-5C>T		splice_region intron	N/A	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104855 AN: 151932 Hom.: 37948 Cov.: 33

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.714

GnomAD2 exomes AF: 0.756 AC: 188682 AN: 249504 AF XY: 0.759

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.788 AC: 1150112 AN: 1460164 Hom.: 456463 Cov.: 39 AF XY: 0.785 AC XY: 570464 AN XY: 726542

African (AFR) AF: 0.432 AC: 14445 AN: 33428

American (AMR) AF: 0.773 AC: 34552 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 20978 AN: 26128

East Asian (EAS) AF: 0.777 AC: 30825 AN: 39694

South Asian (SAS) AF: 0.704 AC: 60667 AN: 86188

European-Finnish (FIN) AF: 0.738 AC: 39386 AN: 53338

Middle Eastern (MID) AF: 0.759 AC: 4378 AN: 5768

European-Non Finnish (NFE) AF: 0.809 AC: 898443 AN: 1110580

Other (OTH) AF: 0.770 AC: 46438 AN: 60336

GnomAD4 genome AF: 0.690 AC: 104887 AN: 152050 Hom.: 37953 Cov.: 33 AF XY: 0.687 AC XY: 51066 AN XY: 74344

African (AFR) AF: 0.451 AC: 18706 AN: 41442

American (AMR) AF: 0.743 AC: 11352 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2738 AN: 3470

East Asian (EAS) AF: 0.799 AC: 4118 AN: 5152

South Asian (SAS) AF: 0.697 AC: 3356 AN: 4818

European-Finnish (FIN) AF: 0.735 AC: 7781 AN: 10592

Middle Eastern (MID) AF: 0.777 AC: 227 AN: 292

European-Non Finnish (NFE) AF: 0.800 AC: 54408 AN: 67976

Other (OTH) AF: 0.712 AC: 1503 AN: 2112

Alfa AF: 0.756 Hom.: 115613

Bravo AF: 0.684

Asia WGS AF: 0.691 AC: 2408 AN: 3478

EpiCase AF: 0.804

EpiControl AF: 0.804

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephalic osteodysplastic primordial dwarfism type II (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.47
PhyloP100		0.36
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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: rs2839226; hg19: chr21-47786494; COSMIC: COSV64031156;