rs2839245

Variant names:

• chr21-46416208-T-C
• rs2839245
• NM_006031.6:c.6290T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46416208-T-C
• chr21-46416208-T-G

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.6290T>C​(p.Leu2097Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,614,020 control chromosomes in the GnomAD database, including 12,097 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L2097L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (4397 hom., cov: 32)
  • Exomes 𝑓: 0.082 (7700 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.677
• Publications: 30 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=2.3597479E-4).
• BP6: Variant 21-46416208-T-C is Benign according to our data. Variant chr21-46416208-T-C is described in ClinVar as Benign. ClinVar VariationId is 138621.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.6290T>C	p.Leu2097Pro	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5936T>C	p.Leu1979Pro	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.6290T>C	p.Leu2097Pro	missense	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.5936T>C	p.Leu1979Pro	missense	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6323T>C	p.Leu2108Pro	missense	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26876 AN: 152062 Hom.: 4392 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0762

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.0958 AC: 24089 AN: 251432 AF XY: 0.0904

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.0823

GnomAD4 exome AF: 0.0817 AC: 119448 AN: 1461840 Hom.: 7700 Cov.: 34 AF XY: 0.0808 AC XY: 58794 AN XY: 727226

African (AFR) AF: 0.456 AC: 15257 AN: 33474

American (AMR) AF: 0.0596 AC: 2667 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 2218 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39700

South Asian (SAS) AF: 0.0849 AC: 7320 AN: 86256

European-Finnish (FIN) AF: 0.103 AC: 5525 AN: 53414

Middle Eastern (MID) AF: 0.0735 AC: 424 AN: 5768

European-Non Finnish (NFE) AF: 0.0720 AC: 80091 AN: 1111978

Other (OTH) AF: 0.0973 AC: 5879 AN: 60392

GnomAD4 genome AF: 0.177 AC: 26914 AN: 152180 Hom.: 4397 Cov.: 32 AF XY: 0.174 AC XY: 12916 AN XY: 74420

African (AFR) AF: 0.434 AC: 17977 AN: 41446

American (AMR) AF: 0.0942 AC: 1441 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 300 AN: 3472

East Asian (EAS) AF: 0.00559 AC: 29 AN: 5188

South Asian (SAS) AF: 0.0920 AC: 444 AN: 4826

European-Finnish (FIN) AF: 0.107 AC: 1136 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0762 AC: 5182 AN: 68010

Other (OTH) AF: 0.167 AC: 352 AN: 2112

Alfa AF: 0.106 Hom.: 5553

Bravo AF: 0.187

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0724 AC: 279

ESP6500AA AF: 0.434 AC: 1913

ESP6500EA AF: 0.0758 AC: 652

ExAC AF: 0.104 AC: 12576

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0706

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	0.053
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.30
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.68
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.024
Sift	Benign	0.34	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.13
ClinPred		0.00077	T
GERP RS		-1.5
Varity_R		0.049
gMVP		0.074
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2839245; hg19: chr21-47836122; COSMIC: COSV64029118; COSMIC: COSV64029118;