chr21-46363740-C-G

Variant names:

• chr21-46363740-C-G
• rs61407822
• NM_006031.6:c.2415C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006031.6(PCNT):​c.2415C>G​(p.Ala805Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,614,106 control chromosomes in the GnomAD database, including 7,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (3523 hom., cov: 33)
  • Exomes 𝑓: 0.026 (3645 hom.)
• Consequence: PCNT NM_006031.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.146
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 21-46363740-C-G is Benign according to our data. Variant chr21-46363740-C-G is described in ClinVar as Benign. ClinVar VariationId is 138616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	NM_006031.6	MANE Select	c.2415C>G	p.Ala805Ala	synonymous	Exon 14 of 47	NP_006022.3
	PCNT	NM_001315529.2		c.2061C>G	p.Ala687Ala	synonymous	Exon 14 of 47	NP_001302458.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.2415C>G	p.Ala805Ala	synonymous	Exon 14 of 47	ENSP00000352572.5
	PCNT	ENST00000480896.5	TSL:1	c.2061C>G	p.Ala687Ala	synonymous	Exon 14 of 47	ENSP00000511989.1
	PCNT	ENST00000695558.1		c.2415C>G	p.Ala805Ala	synonymous	Exon 14 of 48	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19579 AN: 152118 Hom.: 3520 Cov.: 33

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0498 AC: 12511 AN: 251384 AF XY: 0.0450

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00364

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0265 AC: 38739 AN: 1461870 Hom.: 3645 Cov.: 32 AF XY: 0.0267 AC XY: 19434 AN XY: 727242

African (AFR) AF: 0.428 AC: 14342 AN: 33478

American (AMR) AF: 0.0358 AC: 1603 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 384 AN: 26136

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39700

South Asian (SAS) AF: 0.0708 AC: 6111 AN: 86258

European-Finnish (FIN) AF: 0.0203 AC: 1084 AN: 53404

Middle Eastern (MID) AF: 0.0411 AC: 237 AN: 5766

European-Non Finnish (NFE) AF: 0.0109 AC: 12164 AN: 1112008

Other (OTH) AF: 0.0453 AC: 2737 AN: 60396

GnomAD4 genome AF: 0.129 AC: 19619 AN: 152236 Hom.: 3523 Cov.: 33 AF XY: 0.126 AC XY: 9384 AN XY: 74430

African (AFR) AF: 0.406 AC: 16851 AN: 41516

American (AMR) AF: 0.0605 AC: 925 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5178

South Asian (SAS) AF: 0.0825 AC: 398 AN: 4824

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

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 860 AN: 68010

Other (OTH) AF: 0.115 AC: 243 AN: 2114

Alfa AF: 0.0215 Hom.: 94

Bravo AF: 0.143

Asia WGS AF: 0.0920 AC: 318 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0156

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.4
DANN	Benign	0.50
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs61407822; hg19: chr21-47783655;