21-46430241-G-C

Variant names:

• chr21-46430241-G-C
• rs1023160
• NM_006031.6:c.7913+9G>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.7913+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,608,684 control chromosomes in the GnomAD database, including 12,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4500 hom., cov: 33)
  • Exomes 𝑓: 0.082 (7742 hom.)
• Consequence: PCNT NM_006031.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.337
• Publications: 6 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=-0.88).
• BP6: Variant 21-46430241-G-C is Benign according to our data. Variant chr21-46430241-G-C is described in ClinVar as Benign. ClinVar VariationId is 138608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 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.7913+9G>C		intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.7559+9G>C		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.7913+9G>C		intron	N/A	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.7559+9G>C		intron	N/A	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7946+9G>C		intron	N/A	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27095 AN: 152058 Hom.: 4494 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0942

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0902

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.0958 AC: 23762 AN: 247964 AF XY: 0.0904

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.0865

Gnomad EAS exome AF: 0.00311

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.0827

GnomAD4 exome AF: 0.0816 AC: 118900 AN: 1456508 Hom.: 7742 Cov.: 30 AF XY: 0.0807 AC XY: 58502 AN XY: 724686

African (AFR) AF: 0.462 AC: 15391 AN: 33312

American (AMR) AF: 0.0593 AC: 2642 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 2215 AN: 26096

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39672

South Asian (SAS) AF: 0.0841 AC: 7235 AN: 86060

European-Finnish (FIN) AF: 0.103 AC: 5465 AN: 52850

Middle Eastern (MID) AF: 0.0738 AC: 366 AN: 4958

European-Non Finnish (NFE) AF: 0.0719 AC: 79668 AN: 1108800

Other (OTH) AF: 0.0972 AC: 5851 AN: 60178

GnomAD4 genome AF: 0.178 AC: 27135 AN: 152176 Hom.: 4500 Cov.: 33 AF XY: 0.175 AC XY: 13005 AN XY: 74396

African (AFR) AF: 0.439 AC: 18217 AN: 41464

American (AMR) AF: 0.0940 AC: 1438 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 300 AN: 3470

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5180

South Asian (SAS) AF: 0.0900 AC: 434 AN: 4820

European-Finnish (FIN) AF: 0.107 AC: 1134 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0761 AC: 5177 AN: 68002

Other (OTH) AF: 0.167 AC: 353 AN: 2112

Alfa AF: 0.0745 Hom.: 232

Bravo AF: 0.189

Asia WGS AF: 0.104 AC: 362 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.4
DANN	Benign	0.35
PhyloP100		-0.34
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: rs1023160; hg19: chr21-47850155; COSMIC: COSV64029129; COSMIC: COSV64029129;