rs1044998

Variant names:

• chr21-46416481-T-G
• rs1044998
• NM_006031.6:c.6563T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-46416481-T-G
• chr21-46416481-T-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.6563T>G​(p.Met2188Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,613,944 control chromosomes in the GnomAD database, including 12,116 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 0.18 (4412 hom., cov: 32)
  • Exomes 𝑓: 0.082 (7704 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.160
• 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: 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=3.4615397E-4).
• BP6: Variant 21-46416481-T-G is Benign according to our data. Variant chr21-46416481-T-G is described in ClinVar as Benign. ClinVar VariationId is 138624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 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.6563T>G	p.Met2188Arg	missense	Exon 30 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6209T>G	p.Met2070Arg	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.6563T>G	p.Met2188Arg	missense	Exon 30 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6209T>G	p.Met2070Arg	missense	Exon 30 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6596T>G	p.Met2199Arg	missense	Exon 31 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26946 AN: 152094 Hom.: 4407 Cov.: 32

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0943

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.0923

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.0958 AC: 24089 AN: 251338 AF XY: 0.0906

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.0552

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.00315

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0749

Gnomad OTH exome AF: 0.0823

GnomAD4 exome AF: 0.0818 AC: 119506 AN: 1461732 Hom.: 7704 Cov.: 34 AF XY: 0.0809 AC XY: 58823 AN XY: 727192

African (AFR) AF: 0.456 AC: 15253 AN: 33478

American (AMR) AF: 0.0597 AC: 2671 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2217 AN: 26136

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

South Asian (SAS) AF: 0.0848 AC: 7314 AN: 86254

European-Finnish (FIN) AF: 0.104 AC: 5551 AN: 53330

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

European-Non Finnish (NFE) AF: 0.0721 AC: 80126 AN: 1111950

Other (OTH) AF: 0.0974 AC: 5883 AN: 60392

GnomAD4 genome AF: 0.177 AC: 26984 AN: 152212 Hom.: 4412 Cov.: 32 AF XY: 0.174 AC XY: 12951 AN XY: 74426

African (AFR) AF: 0.434 AC: 18035 AN: 41514

American (AMR) AF: 0.0941 AC: 1439 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 300 AN: 3470

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5170

South Asian (SAS) AF: 0.0922 AC: 445 AN: 4826

European-Finnish (FIN) AF: 0.108 AC: 1144 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0763 AC: 5188 AN: 68008

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.119 Hom.: 4159

Bravo AF: 0.187

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0724 AC: 279

ESP6500AA AF: 0.434 AC: 1911

ESP6500EA AF: 0.0758 AC: 652

ExAC AF: 0.104 AC: 12590

Asia WGS AF: 0.104 AC: 362 AN: 3478

EpiCase AF: 0.0702

EpiControl AF: 0.0707

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	0.052
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.4
DANN	Benign	0.39
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.16
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.029
Sift	Benign	0.33	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.12
ClinPred		0.0051	T
GERP RS		-0.74
Varity_R		0.12
gMVP		0.20
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: rs1044998; hg19: chr21-47836395; COSMIC: COSV64034413; COSMIC: COSV64034413;