21-46430570-G-C

Variant names:

• chr21-46430570-G-C
• rs2070426
• NM_006031.6:c.7977G>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.7977G>C​(p.Gln2659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,559,684 control chromosomes in the GnomAD database, including 228,653 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19204 hom., cov: 33)
  • Exomes 𝑓: 0.54 (209449 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.90
• Publications: 47 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=2.4640954E-6).
• BP6: Variant 21-46430570-G-C is Benign according to our data. Variant chr21-46430570-G-C is described in ClinVar as Benign. ClinVar VariationId is 159670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 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.7977G>C	p.Gln2659His	missense	Exon 37 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.7623G>C	p.Gln2541His	missense	Exon 37 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.7977G>C	p.Gln2659His	missense	Exon 37 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.7623G>C	p.Gln2541His	missense	Exon 37 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.8010G>C	p.Gln2670His	missense	Exon 38 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74529 AN: 151918 Hom.: 19196 Cov.: 33

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.526 AC: 90059 AN: 171372 AF XY: 0.533

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.558

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.543 AC: 764307 AN: 1407648 Hom.: 209449 Cov.: 58 AF XY: 0.545 AC XY: 379032 AN XY: 695260

African (AFR) AF: 0.335 AC: 10771 AN: 32178

American (AMR) AF: 0.440 AC: 16196 AN: 36826

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 16469 AN: 25286

East Asian (EAS) AF: 0.673 AC: 24717 AN: 36732

South Asian (SAS) AF: 0.535 AC: 42739 AN: 79884

European-Finnish (FIN) AF: 0.512 AC: 25455 AN: 49728

Middle Eastern (MID) AF: 0.646 AC: 2786 AN: 4316

European-Non Finnish (NFE) AF: 0.547 AC: 593582 AN: 1084422

Other (OTH) AF: 0.542 AC: 31592 AN: 58276

GnomAD4 genome AF: 0.491 AC: 74577 AN: 152036 Hom.: 19204 Cov.: 33 AF XY: 0.489 AC XY: 36296 AN XY: 74300

African (AFR) AF: 0.344 AC: 14270 AN: 41514

American (AMR) AF: 0.481 AC: 7348 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2279 AN: 3470

East Asian (EAS) AF: 0.632 AC: 3252 AN: 5142

South Asian (SAS) AF: 0.534 AC: 2572 AN: 4818

European-Finnish (FIN) AF: 0.499 AC: 5273 AN: 10570

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.554 AC: 37648 AN: 67936

Other (OTH) AF: 0.530 AC: 1117 AN: 2106

Alfa AF: 0.524 Hom.: 6086

Bravo AF: 0.484

TwinsUK AF: 0.550 AC: 2041

ALSPAC AF: 0.544 AC: 2097

ESP6500AA AF: 0.342 AC: 1499

ESP6500EA AF: 0.557 AC: 4764

ExAC AF: 0.453 AC: 51092

Asia WGS AF: 0.571 AC: 1985 AN: 3478

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	0.14
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0020
DANN	Benign	0.89
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.083
Sift	Benign	0.093	T
Sift4G	Uncertain	0.032	D
Polyphen		0.031	B
Vest4		0.066
MutPred		0.16		Loss of stability (P = 0.1486)
MPC		0.34
ClinPred		0.021	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.078
Mutation Taster		=96/4	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: rs2070426; hg19: chr21-47850484; COSMIC: COSV64026155; COSMIC: COSV64026155;