21-46324288-C-T

Variant names:

• chr21-46324288-C-T
• rs80017051
• NM_006031.6:c.54+6C>T

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.54+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0553 in 1,605,538 control chromosomes in the GnomAD database, including 2,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (211 hom., cov: 35)
  • Exomes 𝑓: 0.057 (2662 hom.)
• Consequence: PCNT NM_006031.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008184
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.315
• Publications: 9 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]

C21orf58 (HGNC:1300): (chromosome 21 open reading frame 58)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-46324288-C-T is Benign according to our data. Variant chr21-46324288-C-T is described in ClinVar as Benign. ClinVar VariationId is 138618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0644 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.54+6C>T		splice_region intron	N/A	NP_006022.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCNT	ENST00000359568.10	TSL:1 MANE Select	c.54+6C>T		splice_region intron	N/A	ENSP00000352572.5
	C21orf58	ENST00000956568.1		c.-1550G>A		5_prime_UTR	Exon 1 of 9	ENSP00000626627.1
	PCNT	ENST00000695558.1		c.54+6C>T		splice_region intron	N/A	ENSP00000512015.1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6572 AN: 152208 Hom.: 212 Cov.: 35

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0401

GnomAD2 exomes AF: 0.0443 AC: 10466 AN: 236278 AF XY: 0.0443

Gnomad AFR exome AF: 0.00854

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0475

GnomAD4 exome AF: 0.0566 AC: 82288 AN: 1453214 Hom.: 2662 Cov.: 30 AF XY: 0.0555 AC XY: 40141 AN XY: 722714

African (AFR) AF: 0.00825 AC: 275 AN: 33346

American (AMR) AF: 0.0205 AC: 902 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1432 AN: 25934

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39496

South Asian (SAS) AF: 0.0134 AC: 1143 AN: 85234

European-Finnish (FIN) AF: 0.0854 AC: 4517 AN: 52896

Middle Eastern (MID) AF: 0.0249 AC: 143 AN: 5740

European-Non Finnish (NFE) AF: 0.0641 AC: 70883 AN: 1106462

Other (OTH) AF: 0.0498 AC: 2990 AN: 60008

GnomAD4 genome AF: 0.0431 AC: 6570 AN: 152324 Hom.: 211 Cov.: 35 AF XY: 0.0423 AC XY: 3149 AN XY: 74478

African (AFR) AF: 0.0101 AC: 418 AN: 41586

American (AMR) AF: 0.0262 AC: 401 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00910 AC: 44 AN: 4834

European-Finnish (FIN) AF: 0.0858 AC: 911 AN: 10614

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0660 AC: 4489 AN: 68008

Other (OTH) AF: 0.0397 AC: 84 AN: 2116

Alfa AF: 0.0566 Hom.: 149

Bravo AF: 0.0375

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Microcephalic osteodysplastic primordial dwarfism type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.9
DANN	Benign	0.86
PhyloP100		-0.32
PromoterAI		0.19	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0040
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: rs80017051; hg19: chr21-47744202; COSMIC: COSV52452288; COSMIC: COSV52452288;