chr21-46401674-A-G

Variant names:

• chr21-46401674-A-G
• rs6518291
• NM_006031.6:c.4915A>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.4915A>G​(p.Ile1639Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,280 control chromosomes in the GnomAD database, including 44,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8761 hom., cov: 31)
  • Exomes 𝑓: 0.21 (36046 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.63
• Publications: 41 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=4.7264406E-5).
• BP6: Variant 21-46401674-A-G is Benign according to our data. Variant chr21-46401674-A-G is described in ClinVar as Benign. ClinVar VariationId is 159613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 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.4915A>G	p.Ile1639Val	missense	Exon 26 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.4561A>G	p.Ile1521Val	missense	Exon 26 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.4915A>G	p.Ile1639Val	missense	Exon 26 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.4561A>G	p.Ile1521Val	missense	Exon 26 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.4948A>G	p.Ile1650Val	missense	Exon 27 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46355 AN: 151522 Hom.: 8742 Cov.: 31

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.242 AC: 60698 AN: 251320 AF XY: 0.239

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.212 AC: 309294 AN: 1461640 Hom.: 36046 Cov.: 35 AF XY: 0.214 AC XY: 155690 AN XY: 727140

African (AFR) AF: 0.555 AC: 18590 AN: 33476

American (AMR) AF: 0.222 AC: 9941 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5088 AN: 26130

East Asian (EAS) AF: 0.219 AC: 8679 AN: 39700

South Asian (SAS) AF: 0.296 AC: 25565 AN: 86254

European-Finnish (FIN) AF: 0.261 AC: 13949 AN: 53392

Middle Eastern (MID) AF: 0.238 AC: 1374 AN: 5768

European-Non Finnish (NFE) AF: 0.191 AC: 212304 AN: 1111802

Other (OTH) AF: 0.229 AC: 13804 AN: 60394

GnomAD4 genome AF: 0.306 AC: 46423 AN: 151640 Hom.: 8761 Cov.: 31 AF XY: 0.309 AC XY: 22923 AN XY: 74084

African (AFR) AF: 0.536 AC: 22138 AN: 41288

American (AMR) AF: 0.253 AC: 3859 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3466

East Asian (EAS) AF: 0.198 AC: 1020 AN: 5160

South Asian (SAS) AF: 0.303 AC: 1447 AN: 4780

European-Finnish (FIN) AF: 0.266 AC: 2792 AN: 10498

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13560 AN: 67914

Other (OTH) AF: 0.287 AC: 602 AN: 2100

Alfa AF: 0.234 Hom.: 15125

Bravo AF: 0.312

TwinsUK AF: 0.187 AC: 693

ALSPAC AF: 0.188 AC: 723

ESP6500AA AF: 0.536 AC: 2361

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.249 AC: 30243

Asia WGS AF: 0.309 AC: 1071 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.195

ClinVar

ClinVar submissions

Significance: 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.18
DANN	Benign	0.12
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00049	N
LIST_S2	Benign	0.093	T
MetaRNN	Benign	0.000047	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.81	N
PhyloP100		1.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.18
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.068
ClinPred		0.011	T
GERP RS		1.8
Varity_R		0.015
gMVP		0.020
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: rs6518291; hg19: chr21-47821588; COSMIC: COSV64027435;