NM_006031.6:c.7645G>A

Variant names:

• chr21-46428545-G-A
• rs2839256
• NM_006031.6:c.7645G>A

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.7645G>A​(p.Ala2549Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 1,607,914 control chromosomes in the GnomAD database, including 11,990 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4372 hom., cov: 34)
  • Exomes 𝑓: 0.081 (7618 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.596
• Publications: 21 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 (MetaRNN=4.3970346E-4).
• BP6: Variant 21-46428545-G-A is Benign according to our data. Variant chr21-46428545-G-A is described in ClinVar as Benign. ClinVar VariationId is 138604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.428 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.7645G>A	p.Ala2549Thr	missense	Exon 35 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7291G>A	p.Ala2431Thr	missense	Exon 35 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.7645G>A	p.Ala2549Thr	missense	Exon 35 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.7291G>A	p.Ala2431Thr	missense	Exon 35 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7678G>A	p.Ala2560Thr	missense	Exon 36 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26841 AN: 152186 Hom.: 4365 Cov.: 34

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.00577

Gnomad SAS AF: 0.0902

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.0954 AC: 22605 AN: 237018 AF XY: 0.0903

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.0869

Gnomad EAS exome AF: 0.00314

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0756

Gnomad OTH exome AF: 0.0823

GnomAD4 exome AF: 0.0815 AC: 118564 AN: 1455610 Hom.: 7618 Cov.: 33 AF XY: 0.0806 AC XY: 58363 AN XY: 724206

African (AFR) AF: 0.454 AC: 15183 AN: 33432

American (AMR) AF: 0.0589 AC: 2621 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 2214 AN: 26072

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39646

South Asian (SAS) AF: 0.0841 AC: 7230 AN: 86012

European-Finnish (FIN) AF: 0.104 AC: 5133 AN: 49382

Middle Eastern (MID) AF: 0.0753 AC: 388 AN: 5154

European-Non Finnish (NFE) AF: 0.0719 AC: 79901 AN: 1111278

Other (OTH) AF: 0.0969 AC: 5827 AN: 60136

GnomAD4 genome AF: 0.177 AC: 26885 AN: 152304 Hom.: 4372 Cov.: 34 AF XY: 0.173 AC XY: 12904 AN XY: 74480

African (AFR) AF: 0.433 AC: 17984 AN: 41550

American (AMR) AF: 0.0929 AC: 1422 AN: 15304

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

East Asian (EAS) AF: 0.00579 AC: 30 AN: 5184

South Asian (SAS) AF: 0.0900 AC: 435 AN: 4832

European-Finnish (FIN) AF: 0.107 AC: 1135 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0761 AC: 5176 AN: 68022

Other (OTH) AF: 0.166 AC: 350 AN: 2114

Alfa AF: 0.0869 Hom.: 1827

Bravo AF: 0.186

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0721 AC: 278

ESP6500AA AF: 0.428 AC: 1879

ESP6500EA AF: 0.0762 AC: 654

ExAC AF: 0.102 AC: 12233

Asia WGS AF: 0.104 AC: 361 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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.7
DANN	Benign	0.69
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.00044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.53	N
PhyloP100		0.60
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.027
Sift	Benign	0.88	T
Sift4G	Benign	0.55	T
Polyphen		0.46	P
Vest4		0.042
MPC		0.36
ClinPred		0.0085	T
GERP RS		0.66
Varity_R		0.030
gMVP		0.023
Mutation Taster		=99/1	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: rs2839256; hg19: chr21-47848459; COSMIC: COSV64027272; COSMIC: COSV64027272;