rs35848602

Variant names:

• chr21-46418268-C-G
• rs35848602
• NM_006031.6:c.6986C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006031.6(PCNT):​c.6986C>G​(p.Pro2329Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,608,660 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (16 hom.)
• Consequence: PCNT NM_006031.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.294
• Publications: 11 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=0.0044974685).
• BP6: Variant 21-46418268-C-G is Benign according to our data. Variant chr21-46418268-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00597 (910/152320) while in subpopulation AFR AF = 0.0152 (632/41556). AF 95% confidence interval is 0.0142. There are 7 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.6986C>G	p.Pro2329Arg	missense	Exon 31 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.6632C>G	p.Pro2211Arg	missense	Exon 31 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.6986C>G	p.Pro2329Arg	missense	Exon 31 of 47	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.6632C>G	p.Pro2211Arg	missense	Exon 31 of 47	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.7019C>G	p.Pro2340Arg	missense	Exon 32 of 48	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 909 AN: 152202 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00289 AC: 727 AN: 251256 AF XY: 0.00248

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00146 AC: 2130 AN: 1456340 Hom.: 16 Cov.: 28 AF XY: 0.00139 AC XY: 1011 AN XY: 724954

African (AFR) AF: 0.0145 AC: 483 AN: 33308

American (AMR) AF: 0.00409 AC: 183 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 398 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86124

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53410

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5756

European-Non Finnish (NFE) AF: 0.000719 AC: 796 AN: 1107042

Other (OTH) AF: 0.00360 AC: 217 AN: 60220

GnomAD4 genome AF: 0.00597 AC: 910 AN: 152320 Hom.: 7 Cov.: 33 AF XY: 0.00608 AC XY: 453 AN XY: 74490

African (AFR) AF: 0.0152 AC: 632 AN: 41556

American (AMR) AF: 0.00738 AC: 113 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68038

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00382 Hom.: 2

Bravo AF: 0.00697

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Microcephalic osteodysplastic primordial dwarfism type II (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.29
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.039
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.51
MPC		0.44
ClinPred		0.034	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.19
Mutation Taster		=99/1	polymorphism

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: rs35848602; hg19: chr21-47838182;