21-46413003-G-C

Variant names:

• chr21-46413003-G-C
• rs10222116
• NM_006031.6:c.6150+11G>C

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.6150+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,414,308 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCNT NM_006031.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.316
• Publications: 0 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 (BayesDel_noAF=-0.83).
• BP6: Variant 21-46413003-G-C is Benign according to our data. Variant chr21-46413003-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00103 (1455/1414308) while in subpopulation AFR AF = 0.0135 (428/31758). AF 95% confidence interval is 0.0124. There are 11 homozygotes in GnomAdExome4. There are 718 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.6150+11G>C		intron	N/A	NP_006022.3
	PCNT	NM_001315529.2		c.5796+11G>C		intron	N/A	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.6150+11G>C		intron	N/A	ENSP00000352572.5	O95613-1
	PCNT	ENST00000480896.5	TSL:1	c.5796+11G>C		intron	N/A	ENSP00000511989.1	O95613-2
	PCNT	ENST00000695558.1		c.6183+11G>C		intron	N/A	ENSP00000512015.1	A0A8Q3SHZ3

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1466 AN: 119418 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00841

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00318

Gnomad MID AF: 0.0144

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00425 AC: 941 AN: 221224 AF XY: 0.00354

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00599

Gnomad EAS exome AF: 0.000411

Gnomad FIN exome AF: 0.000444

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00103 AC: 1455 AN: 1414308 Hom.: 11 Cov.: 33 AF XY: 0.00102 AC XY: 718 AN XY: 703536

African (AFR) AF: 0.0135 AC: 428 AN: 31758

American (AMR) AF: 0.00282 AC: 121 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.00391 AC: 99 AN: 25318

East Asian (EAS) AF: 0.000209 AC: 8 AN: 38254

South Asian (SAS) AF: 0.000545 AC: 46 AN: 84470

European-Finnish (FIN) AF: 0.000324 AC: 14 AN: 43186

Middle Eastern (MID) AF: 0.00195 AC: 11 AN: 5630

European-Non Finnish (NFE) AF: 0.000539 AC: 584 AN: 1084326

Other (OTH) AF: 0.00246 AC: 144 AN: 58426

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0123 AC: 1471 AN: 119518 Hom.: 14 Cov.: 33 AF XY: 0.0121 AC XY: 708 AN XY: 58376

African (AFR) AF: 0.0318 AC: 1053 AN: 33124

American (AMR) AF: 0.0112 AC: 137 AN: 12226

Ashkenazi Jewish (ASJ) AF: 0.00841 AC: 23 AN: 2736

East Asian (EAS) AF: 0.00353 AC: 13 AN: 3680

South Asian (SAS) AF: 0.00229 AC: 8 AN: 3498

European-Finnish (FIN) AF: 0.00318 AC: 26 AN: 8170

Middle Eastern (MID) AF: 0.0153 AC: 3 AN: 196

European-Non Finnish (NFE) AF: 0.00349 AC: 187 AN: 53552

Other (OTH) AF: 0.0125 AC: 21 AN: 1678

Alfa AF: 0.00135 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephalic osteodysplastic primordial dwarfism type II (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.32
PhyloP100		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs10222116; hg19: chr21-47832917; COSMIC: COSV64026201;