rs61735543

Variant names:

• chr21-46411608-G-A
• rs61735543
• NM_006031.6:c.5535G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.5535G>A​(p.Arg1845Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,006 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (635 hom., cov: 34)
  • Exomes 𝑓: 0.019 (952 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.90
• Publications: 6 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Moyamoya disease

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 21-46411608-G-A is Benign according to our data. Variant chr21-46411608-G-A is described in ClinVar as Benign. ClinVar VariationId is 138620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 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.5535G>A	p.Arg1845Arg	synonymous	Exon 28 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.5181G>A	p.Arg1727Arg	synonymous	Exon 28 of 47	NP_001302458.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.5535G>A	p.Arg1845Arg	synonymous	Exon 28 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.5181G>A	p.Arg1727Arg	synonymous	Exon 28 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.5568G>A	p.Arg1856Arg	synonymous	Exon 29 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9227 AN: 152172 Hom.: 631 Cov.: 34

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0823

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0314 AC: 7774 AN: 247432 AF XY: 0.0317

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.00289

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0188 AC: 27402 AN: 1460716 Hom.: 952 Cov.: 34 AF XY: 0.0200 AC XY: 14546 AN XY: 726714

African (AFR) AF: 0.179 AC: 6000 AN: 33458

American (AMR) AF: 0.0194 AC: 867 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 342 AN: 26122

East Asian (EAS) AF: 0.00159 AC: 63 AN: 39692

South Asian (SAS) AF: 0.0707 AC: 6101 AN: 86256

European-Finnish (FIN) AF: 0.0203 AC: 1067 AN: 52492

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5768

European-Non Finnish (NFE) AF: 0.0100 AC: 11113 AN: 1111834

Other (OTH) AF: 0.0283 AC: 1706 AN: 60378

GnomAD4 genome AF: 0.0607 AC: 9251 AN: 152290 Hom.: 635 Cov.: 34 AF XY: 0.0604 AC XY: 4499 AN XY: 74466

African (AFR) AF: 0.172 AC: 7152 AN: 41534

American (AMR) AF: 0.0304 AC: 466 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5184

South Asian (SAS) AF: 0.0820 AC: 396 AN: 4832

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10624

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 762 AN: 68010

Other (OTH) AF: 0.0671 AC: 142 AN: 2116

Alfa AF: 0.0325 Hom.: 172

Bravo AF: 0.0657

Asia WGS AF: 0.0800 AC: 279 AN: 3476

EpiCase AF: 0.0126

EpiControl AF: 0.0134

ClinVar

ClinVar submissions as Germline

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)
-	-	1	PCNT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs61735543; hg19: chr21-47831522;