chr21-46416633-T-C

Variant names:

• chr21-46416633-T-C
• rs35346764
• NM_006031.6:c.6715T>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.6715T>C​(p.Trp2239Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,570,834 control chromosomes in the GnomAD database, including 12,147 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W2239S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (4565 hom., cov: 32)
  • Exomes 𝑓: 0.082 (7582 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.142
• Publications: 17 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=1.8361211E-4).
• BP6: Variant 21-46416633-T-C is Benign according to our data. Variant chr21-46416633-T-C is described in ClinVar as Benign. ClinVar VariationId is 138626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 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.6715T>C	p.Trp2239Arg	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6361T>C	p.Trp2121Arg	missense	Exon 30 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.6715T>C	p.Trp2239Arg	missense	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6361T>C	p.Trp2121Arg	missense	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6748T>C	p.Trp2250Arg	missense	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27268 AN: 152018 Hom.: 4560 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0951

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.0936

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0765

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.0972 AC: 20538 AN: 211278 AF XY: 0.0913

Gnomad AFR exome AF: 0.452

Gnomad AMR exome AF: 0.0543

Gnomad ASJ exome AF: 0.0853

Gnomad EAS exome AF: 0.00316

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0838

GnomAD4 exome AF: 0.0817 AC: 115889 AN: 1418698 Hom.: 7582 Cov.: 34 AF XY: 0.0808 AC XY: 56670 AN XY: 701322

African (AFR) AF: 0.464 AC: 14896 AN: 32122

American (AMR) AF: 0.0589 AC: 2352 AN: 39928

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 1913 AN: 22826

East Asian (EAS) AF: 0.00170 AC: 67 AN: 39420

South Asian (SAS) AF: 0.0843 AC: 6600 AN: 78314

European-Finnish (FIN) AF: 0.103 AC: 5198 AN: 50334

Middle Eastern (MID) AF: 0.0727 AC: 398 AN: 5478

European-Non Finnish (NFE) AF: 0.0721 AC: 78741 AN: 1091856

Other (OTH) AF: 0.0980 AC: 5724 AN: 58420

GnomAD4 genome AF: 0.179 AC: 27306 AN: 152136 Hom.: 4565 Cov.: 32 AF XY: 0.176 AC XY: 13119 AN XY: 74396

African (AFR) AF: 0.442 AC: 18336 AN: 41466

American (AMR) AF: 0.0948 AC: 1451 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 300 AN: 3466

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5170

South Asian (SAS) AF: 0.0935 AC: 451 AN: 4826

European-Finnish (FIN) AF: 0.107 AC: 1135 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0764 AC: 5196 AN: 67974

Other (OTH) AF: 0.168 AC: 355 AN: 2114

Alfa AF: 0.132 Hom.: 1181

Bravo AF: 0.189

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0724 AC: 279

ESP6500AA AF: 0.413 AC: 1811

ESP6500EA AF: 0.0731 AC: 627

ExAC AF: 0.100 AC: 12129

Asia WGS AF: 0.106 AC: 367 AN: 3478

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
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.7
DANN	Benign	0.74
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.14
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.021
Sift	Benign	0.36	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.18		Loss of catalytic residue at W2239 (P = 0.0018)
MPC		0.15
ClinPred		0.0029	T
GERP RS		1.3
Varity_R		0.038
gMVP		0.21
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: rs35346764; hg19: chr21-47836547; COSMIC: COSV64033642; COSMIC: COSV64033642;