chr21-46353263-C-T

Variant names:

• chr21-46353263-C-T
• rs2249060
• NM_006031.6:c.1616C>T

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.1616C>T​(p.Thr539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,838 control chromosomes in the GnomAD database, including 14,670 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1357 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13313 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.244
• Publications: 40 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, 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 (MetaRNN=0.0035569966).
• BP6: Variant 21-46353263-C-T is Benign according to our data. Variant chr21-46353263-C-T is described in ClinVar as Benign. ClinVar VariationId is 159567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 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.1616C>T	p.Thr539Ile	missense	Exon 10 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.1262C>T	p.Thr421Ile	missense	Exon 10 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.1616C>T	p.Thr539Ile	missense	Exon 10 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.1262C>T	p.Thr421Ile	missense	Exon 10 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.1616C>T	p.Thr539Ile	missense	Exon 10 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19766 AN: 152074 Hom.: 1355 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.147 AC: 36930 AN: 251422 AF XY: 0.150

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.130 AC: 190656 AN: 1461646 Hom.: 13313 Cov.: 35 AF XY: 0.134 AC XY: 97237 AN XY: 727122

African (AFR) AF: 0.102 AC: 3404 AN: 33474

American (AMR) AF: 0.167 AC: 7473 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2902 AN: 26134

East Asian (EAS) AF: 0.216 AC: 8558 AN: 39700

South Asian (SAS) AF: 0.209 AC: 18018 AN: 86246

European-Finnish (FIN) AF: 0.158 AC: 8454 AN: 53384

Middle Eastern (MID) AF: 0.162 AC: 937 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 132952 AN: 1111838

Other (OTH) AF: 0.132 AC: 7958 AN: 60382

GnomAD4 genome AF: 0.130 AC: 19788 AN: 152192 Hom.: 1357 Cov.: 32 AF XY: 0.136 AC XY: 10136 AN XY: 74412

African (AFR) AF: 0.103 AC: 4284 AN: 41532

American (AMR) AF: 0.161 AC: 2462 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3472

East Asian (EAS) AF: 0.192 AC: 993 AN: 5176

South Asian (SAS) AF: 0.209 AC: 1007 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10592

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8445 AN: 67998

Other (OTH) AF: 0.122 AC: 258 AN: 2114

Alfa AF: 0.126 Hom.: 4759

Bravo AF: 0.127

TwinsUK AF: 0.122 AC: 452

ALSPAC AF: 0.118 AC: 453

ESP6500AA AF: 0.104 AC: 460

ESP6500EA AF: 0.124 AC: 1070

ExAC AF: 0.147 AC: 17838

Asia WGS AF: 0.199 AC: 688 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.125

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.4
DANN	Benign	0.88
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.24
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.015
Sift	Benign	0.11	T
Sift4G	Benign	0.38	T
Polyphen		0.14	B
Vest4		0.027
MPC		0.14
ClinPred		0.0066	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.044
Mutation Taster		=98/2	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: rs2249060; hg19: chr21-47773177; COSMIC: COSV64026400; COSMIC: COSV64026400;