rs747401688

Variant names:

• chr21-46324154-G-A
• rs747401688
• ENST00000956568.1:c.-1416C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000956568.1(C21orf58):​c.-1416C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000822 in 1,242,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: C21orf58 ENST00000956568.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

Genes affected

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

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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000956568.1. 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.-75G>A		upstream_gene	N/A	NP_006022.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf58	ENST00000956568.1		c.-1416C>T		5_prime_UTR	Exon 1 of 9	ENSP00000626627.1
	PCNT	ENST00000466474.6	TSL:3	n.-75G>A		non_coding_transcript_exon	Exon 1 of 18	ENSP00000511987.1	A0A8Q3SI04
	PCNT	ENST00000490468.5	TSL:5	n.-75G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000515241.1	A0A8V8TQ91

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152186 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000873 AC: 952 AN: 1090458 Hom.: 0 Cov.: 14 AF XY: 0.000836 AC XY: 463 AN XY: 553726

African (AFR) AF: 0.000189 AC: 5 AN: 26490

American (AMR) AF: 0.000352 AC: 13 AN: 36902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23206

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36106

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74482

European-Finnish (FIN) AF: 0.000473 AC: 23 AN: 48586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4740

European-Non Finnish (NFE) AF: 0.00111 AC: 877 AN: 792050

Other (OTH) AF: 0.000668 AC: 32 AN: 47896

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152304 Hom.: 0 Cov.: 35 AF XY: 0.000336 AC XY: 25 AN XY: 74474

African (AFR) AF: 0.000216 AC: 9 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000502

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Microcephalic osteodysplastic primordial dwarfism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.97
PhyloP100		2.4
PromoterAI		-0.093	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=286/14	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: rs747401688; hg19: chr21-47744068;