21-46443844-A-C

Variant names:

• chr21-46443844-A-C
• rs2073380
• NM_006031.6:c.9735A>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.9735A>C​(p.Arg3245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,004 control chromosomes in the GnomAD database, including 40,037 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 0.19 (3087 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36950 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0960
• 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: 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=0.0011502206).
• BP6: Variant 21-46443844-A-C is Benign according to our data. Variant chr21-46443844-A-C is described in ClinVar as Benign. ClinVar VariationId is 159697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 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.9735A>C	p.Arg3245Ser	missense	Exon 45 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.9144A>C	p.Arg3048Ser	missense	Exon 45 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.9735A>C	p.Arg3245Ser	missense	Exon 45 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.9144A>C	p.Arg3048Ser	missense	Exon 45 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.9768A>C	p.Arg3256Ser	missense	Exon 46 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28256 AN: 152032 Hom.: 3089 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.205

GnomAD2 exomes AF: 0.225 AC: 56476 AN: 251232 AF XY: 0.229

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.434

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.219 AC: 319941 AN: 1460854 Hom.: 36950 Cov.: 34 AF XY: 0.221 AC XY: 160506 AN XY: 726764

African (AFR) AF: 0.0750 AC: 2508 AN: 33454

American (AMR) AF: 0.163 AC: 7296 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6059 AN: 26134

East Asian (EAS) AF: 0.445 AC: 17672 AN: 39700

South Asian (SAS) AF: 0.233 AC: 20090 AN: 86210

European-Finnish (FIN) AF: 0.246 AC: 13161 AN: 53400

Middle Eastern (MID) AF: 0.273 AC: 1436 AN: 5260

European-Non Finnish (NFE) AF: 0.214 AC: 238069 AN: 1111656

Other (OTH) AF: 0.226 AC: 13650 AN: 60316

GnomAD4 genome AF: 0.186 AC: 28257 AN: 152150 Hom.: 3087 Cov.: 32 AF XY: 0.186 AC XY: 13867 AN XY: 74388

African (AFR) AF: 0.0800 AC: 3321 AN: 41528

American (AMR) AF: 0.166 AC: 2536 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2207 AN: 5158

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4820

European-Finnish (FIN) AF: 0.241 AC: 2555 AN: 10594

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14844 AN: 67970

Other (OTH) AF: 0.205 AC: 432 AN: 2112

Alfa AF: 0.213 Hom.: 5476

Bravo AF: 0.178

TwinsUK AF: 0.212 AC: 785

ALSPAC AF: 0.218 AC: 842

ESP6500AA AF: 0.0808 AC: 356

ESP6500EA AF: 0.215 AC: 1849

ExAC AF: 0.228 AC: 27660

Asia WGS AF: 0.302 AC: 1049 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.8
DANN	Benign	0.40
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.096
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.013
Sift	Benign	0.73	T
Sift4G	Benign	0.70	T
Polyphen		0.010	B
Vest4		0.039
MutPred		0.32		Gain of phosphorylation at R3245 (P = 0.0025)
MPC		0.29
ClinPred		0.0098	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.25
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: rs2073380; hg19: chr21-47863757; COSMIC: COSV64024960; COSMIC: COSV64024960;