chr21-46302477-A-G

Variant names:

• chr21-46302477-A-G
• rs1556337
• NM_058180.5:c.813+8T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_058180.5(C21orf58):​c.813+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,596,832 control chromosomes in the GnomAD database, including 373,867 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (29835 hom., cov: 32)
  • Exomes 𝑓: 0.69 (344032 hom.)
• Consequence: C21orf58 NM_058180.5 splice_region, intron
• Scores: Splicing: ADA: 0.000007724
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 13 publications found

Genes affected

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

YBEY (HGNC:1299): (ybeY metalloendoribonuclease) This gene encodes a highly conserved metalloprotein. A similar protein in bacteria acts as an endoribonuclease, and is thought to function in ribosomal RNA maturation and ribosome assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058180.5. 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
	C21orf58	NM_058180.5	MANE Select	c.813+8T>C		splice_region intron	N/A	NP_478060.2
	C21orf58	NM_001286462.2		c.495+8T>C		splice_region intron	N/A	NP_001273391.1
	C21orf58	NM_001286463.1		c.495+8T>C		splice_region intron	N/A	NP_001273392.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf58	ENST00000291691.12	TSL:2 MANE Select	c.813+8T>C		splice_region intron	N/A	ENSP00000291691.8
	C21orf58	ENST00000417060.5	TSL:1	c.699+8T>C		splice_region intron	N/A	ENSP00000402356.1
	C21orf58	ENST00000397682.7	TSL:1	c.495+8T>C		splice_region intron	N/A	ENSP00000380798.3

Frequencies

GnomAD3 genomes AF: 0.613 AC: 93087 AN: 151804 Hom.: 29820 Cov.: 32

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.614

GnomAD2 exomes AF: 0.654 AC: 152655 AN: 233452 AF XY: 0.654

Gnomad AFR exome AF: 0.412

Gnomad AMR exome AF: 0.711

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.686 AC: 990578 AN: 1444910 Hom.: 344032 Cov.: 30 AF XY: 0.683 AC XY: 490951 AN XY: 718576

African (AFR) AF: 0.409 AC: 13533 AN: 33128

American (AMR) AF: 0.703 AC: 30578 AN: 43524

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 17487 AN: 25860

East Asian (EAS) AF: 0.377 AC: 14849 AN: 39380

South Asian (SAS) AF: 0.613 AC: 51900 AN: 84610

European-Finnish (FIN) AF: 0.718 AC: 37904 AN: 52822

Middle Eastern (MID) AF: 0.634 AC: 3535 AN: 5580

European-Non Finnish (NFE) AF: 0.710 AC: 781109 AN: 1100272

Other (OTH) AF: 0.664 AC: 39683 AN: 59734

GnomAD4 genome AF: 0.613 AC: 93142 AN: 151922 Hom.: 29835 Cov.: 32 AF XY: 0.612 AC XY: 45439 AN XY: 74224

African (AFR) AF: 0.425 AC: 17591 AN: 41412

American (AMR) AF: 0.669 AC: 10221 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2326 AN: 3470

East Asian (EAS) AF: 0.440 AC: 2250 AN: 5110

South Asian (SAS) AF: 0.598 AC: 2878 AN: 4812

European-Finnish (FIN) AF: 0.716 AC: 7577 AN: 10582

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48202 AN: 67948

Other (OTH) AF: 0.615 AC: 1296 AN: 2108

Alfa AF: 0.672 Hom.: 32064

Bravo AF: 0.601

Asia WGS AF: 0.523 AC: 1824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.15
DANN	Benign	0.53
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000077
dbscSNV1_RF	Benign	0.0
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: rs1556337; hg19: chr21-47722391; COSMIC: COSV52448887; COSMIC: COSV52448887;