rs6518289

Variant names:

• chr21-46367087-T-C
• rs6518289
• NM_006031.6:c.3113T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46367087-T-C
• chr21-46367087-T-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.3113T>C​(p.Val1038Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,613,630 control chromosomes in the GnomAD database, including 610,688 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 0.87 (57696 hom., cov: 32)
  • Exomes 𝑓: 0.87 (552992 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.194
• Publications: 46 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=9.449875E-7).
• BP6: Variant 21-46367087-T-C is Benign according to our data. Variant chr21-46367087-T-C is described in ClinVar as Benign. ClinVar VariationId is 159581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.891 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.3113T>C	p.Val1038Ala	missense	Exon 15 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.2759T>C	p.Val920Ala	missense	Exon 15 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.3113T>C	p.Val1038Ala	missense	Exon 15 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.2759T>C	p.Val920Ala	missense	Exon 15 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.3113T>C	p.Val1038Ala	missense	Exon 15 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132358 AN: 152088 Hom.: 57659 Cov.: 32

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.838

Gnomad ASJ AF: 0.876

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.842

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.875

GnomAD2 exomes AF: 0.853 AC: 212763 AN: 249528 AF XY: 0.850

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.834

Gnomad ASJ exome AF: 0.888

Gnomad EAS exome AF: 0.816

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.869 AC: 1270245 AN: 1461424 Hom.: 552992 Cov.: 64 AF XY: 0.866 AC XY: 629436 AN XY: 726984

African (AFR) AF: 0.900 AC: 30128 AN: 33480

American (AMR) AF: 0.833 AC: 37234 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 23241 AN: 26134

East Asian (EAS) AF: 0.779 AC: 30914 AN: 39698

South Asian (SAS) AF: 0.788 AC: 68001 AN: 86256

European-Finnish (FIN) AF: 0.842 AC: 44603 AN: 52992

Middle Eastern (MID) AF: 0.836 AC: 4820 AN: 5768

European-Non Finnish (NFE) AF: 0.880 AC: 978885 AN: 1111980

Other (OTH) AF: 0.868 AC: 52419 AN: 60392

GnomAD4 genome AF: 0.870 AC: 132453 AN: 152206 Hom.: 57696 Cov.: 32 AF XY: 0.864 AC XY: 64292 AN XY: 74408

African (AFR) AF: 0.898 AC: 37338 AN: 41558

American (AMR) AF: 0.838 AC: 12820 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.876 AC: 3038 AN: 3470

East Asian (EAS) AF: 0.807 AC: 4158 AN: 5150

South Asian (SAS) AF: 0.788 AC: 3803 AN: 4824

European-Finnish (FIN) AF: 0.842 AC: 8922 AN: 10592

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59544 AN: 68004

Other (OTH) AF: 0.876 AC: 1850 AN: 2112

Alfa AF: 0.873 Hom.: 164481

Bravo AF: 0.873

TwinsUK AF: 0.877 AC: 3253

ALSPAC AF: 0.883 AC: 3404

ESP6500AA AF: 0.898 AC: 3958

ESP6500EA AF: 0.875 AC: 7527

ExAC AF: 0.852 AC: 103477

Asia WGS AF: 0.800 AC: 2784 AN: 3478

EpiCase AF: 0.873

EpiControl AF: 0.874

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephalic osteodysplastic primordial dwarfism type II (4)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0040
DANN	Benign	0.35
DEOGEN2	Benign	0.031	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	9.4e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.19
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Benign	0.64	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.097
ClinPred		0.025	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.047
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: rs6518289; hg19: chr21-47787002; COSMIC: COSV64031868;