rs35147998

Variant names:

• chr21-46432171-G-A
• rs35147998
• NM_006031.6:c.8707G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46432171-G-A
• chr21-46432171-G-C
• chr21-46432171-G-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.8707G>A​(p.Ala2903Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0707 in 1,613,078 control chromosomes in the GnomAD database, including 4,377 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2903P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.056 (305 hom., cov: 34)
  • Exomes 𝑓: 0.072 (4072 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.30
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019298196).
• BP6: Variant 21-46432171-G-A is Benign according to our data. Variant chr21-46432171-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 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.8707G>A	p.Ala2903Thr	missense	Exon 38 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.8160+193G>A		intron	N/A	NP_001302458.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.8707G>A	p.Ala2903Thr	missense	Exon 38 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.8160+193G>A		intron	N/A	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.8740G>A	p.Ala2914Thr	missense	Exon 39 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.0564 AC: 8584 AN: 152250 Hom.: 305 Cov.: 34

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.0835

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0420

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0713

GnomAD2 exomes AF: 0.0610 AC: 15089 AN: 247396 AF XY: 0.0619

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0892

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0828

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0722 AC: 105536 AN: 1460710 Hom.: 4072 Cov.: 37 AF XY: 0.0715 AC XY: 51964 AN XY: 726584

African (AFR) AF: 0.0132 AC: 441 AN: 33458

American (AMR) AF: 0.0368 AC: 1646 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 2266 AN: 26134

East Asian (EAS) AF: 0.0126 AC: 499 AN: 39692

South Asian (SAS) AF: 0.0458 AC: 3947 AN: 86206

European-Finnish (FIN) AF: 0.0760 AC: 4033 AN: 53054

Middle Eastern (MID) AF: 0.0564 AC: 305 AN: 5412

European-Non Finnish (NFE) AF: 0.0796 AC: 88550 AN: 1111754

Other (OTH) AF: 0.0638 AC: 3849 AN: 60306

GnomAD4 genome AF: 0.0563 AC: 8582 AN: 152368 Hom.: 305 Cov.: 34 AF XY: 0.0560 AC XY: 4170 AN XY: 74502

African (AFR) AF: 0.0161 AC: 669 AN: 41600

American (AMR) AF: 0.0596 AC: 912 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0835 AC: 290 AN: 3472

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5190

South Asian (SAS) AF: 0.0418 AC: 202 AN: 4830

European-Finnish (FIN) AF: 0.0741 AC: 787 AN: 10616

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0801 AC: 5448 AN: 68032

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0745 Hom.: 1611

Bravo AF: 0.0533

TwinsUK AF: 0.0841 AC: 312

ALSPAC AF: 0.0791 AC: 305

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0828 AC: 712

ExAC AF: 0.0612 AC: 7432

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0819

EpiControl AF: 0.0838

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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)
-	-	1	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.53
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.083
Sift	Benign	0.23	T
Sift4G	Benign	0.46	T
Polyphen		0.089	B
Vest4		0.056
MPC		0.36
ClinPred		0.017	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.058
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: rs35147998; hg19: chr21-47852085; COSMIC: COSV64025476; COSMIC: COSV64025476;