NM_006031.6:c.7536G>A

Variant names:

• chr21-46428436-G-A
• rs61735818
• NM_006031.6:c.7536G>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.7536G>A​(p.Pro2512Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,612,398 control chromosomes in the GnomAD database, including 2,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (226 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2521 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.59
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-46428436-G-A is Benign according to our data. Variant chr21-46428436-G-A is described in ClinVar as Benign. ClinVar VariationId is 138603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0622 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.7536G>A	p.Pro2512Pro	synonymous	Exon 35 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7182G>A	p.Pro2394Pro	synonymous	Exon 35 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.7536G>A	p.Pro2512Pro	synonymous	Exon 35 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.7182G>A	p.Pro2394Pro	synonymous	Exon 35 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.7569G>A	p.Pro2523Pro	synonymous	Exon 36 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7234 AN: 152240 Hom.: 227 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0850

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0493

GnomAD2 exomes AF: 0.0459 AC: 11394 AN: 248050 AF XY: 0.0455

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0718

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0552 AC: 80630 AN: 1460040 Hom.: 2521 Cov.: 33 AF XY: 0.0542 AC XY: 39372 AN XY: 726302

African (AFR) AF: 0.0227 AC: 759 AN: 33470

American (AMR) AF: 0.0239 AC: 1068 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1854 AN: 26092

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0139 AC: 1196 AN: 86152

European-Finnish (FIN) AF: 0.0835 AC: 4352 AN: 52104

Middle Eastern (MID) AF: 0.0322 AC: 185 AN: 5748

European-Non Finnish (NFE) AF: 0.0613 AC: 68114 AN: 1111772

Other (OTH) AF: 0.0513 AC: 3098 AN: 60338

GnomAD4 genome AF: 0.0475 AC: 7232 AN: 152358 Hom.: 226 Cov.: 33 AF XY: 0.0470 AC XY: 3502 AN XY: 74500

African (AFR) AF: 0.0252 AC: 1047 AN: 41590

American (AMR) AF: 0.0334 AC: 512 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4832

European-Finnish (FIN) AF: 0.0850 AC: 903 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4340 AN: 68034

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0495 Hom.: 119

Bravo AF: 0.0429

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0558

EpiControl AF: 0.0555

ClinVar

ClinVar submissions as Germline

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	0.058
DANN	Benign	0.41
PhyloP100		-3.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61735818; hg19: chr21-47848350; COSMIC: COSV64033659; COSMIC: COSV64033659;