21-46302071-ATGGTGGTGGTGG-ATGGTGGTGG

Variant names:

• chr21-46302071-ATGG-A
• rs71318063
• NM_058180.5:c.894_896delCCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_058180.5(C21orf58):​c.894_896delCCA​(p.His299del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,500,426 control chromosomes in the GnomAD database, including 18 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0057 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: C21orf58 NM_058180.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• Publications: 12 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_058180.5
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00575 (871/151518) while in subpopulation AFR AF = 0.0197 (815/41384). AF 95% confidence interval is 0.0186. There are 12 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf58	NM_058180.5	MANE Select	c.894_896delCCA	p.His299del	disruptive_inframe_deletion	Exon 8 of 8	NP_478060.2
	C21orf58	NM_001286462.2		c.576_578delCCA	p.His193del	disruptive_inframe_deletion	Exon 8 of 9	NP_001273391.1	P58505-3
	C21orf58	NM_001286463.1		c.576_578delCCA	p.His193del	disruptive_inframe_deletion	Exon 7 of 7	NP_001273392.1	P58505-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C21orf58	ENST00000291691.12	TSL:2 MANE Select	c.894_896delCCA	p.His299del	disruptive_inframe_deletion	Exon 8 of 8	ENSP00000291691.8	P58505-1
	C21orf58	ENST00000417060.5	TSL:1	c.780_782delCCA	p.His261del	disruptive_inframe_deletion	Exon 7 of 8	ENSP00000402356.1	H7C1T9
	C21orf58	ENST00000397682.7	TSL:1	c.576_578delCCA	p.His193del	disruptive_inframe_deletion	Exon 8 of 9	ENSP00000380798.3	P58505-3

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 869 AN: 151402 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00483

GnomAD2 exomes AF: 0.00366 AC: 408 AN: 111606 AF XY: 0.00349

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00301

Gnomad FIN exome AF: 0.00377

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00111 AC: 1504 AN: 1348908 Hom.: 6 AF XY: 0.00112 AC XY: 745 AN XY: 663956

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0223 AC: 680 AN: 30546

American (AMR) AF: 0.00308 AC: 99 AN: 32124

Ashkenazi Jewish (ASJ) AF: 0.000994 AC: 24 AN: 24146

East Asian (EAS) AF: 0.000648 AC: 22 AN: 33958

South Asian (SAS) AF: 0.000892 AC: 67 AN: 75154

European-Finnish (FIN) AF: 0.000980 AC: 41 AN: 41822

Middle Eastern (MID) AF: 0.00165 AC: 9 AN: 5466

European-Non Finnish (NFE) AF: 0.000413 AC: 433 AN: 1049670

Other (OTH) AF: 0.00230 AC: 129 AN: 56022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00575 AC: 871 AN: 151518 Hom.: 12 Cov.: 0 AF XY: 0.00551 AC XY: 408 AN XY: 74000

African (AFR) AF: 0.0197 AC: 815 AN: 41384

American (AMR) AF: 0.00210 AC: 32 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67750

Other (OTH) AF: 0.00478 AC: 10 AN: 2094

Alfa AF: 0.00380 Hom.: 491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs71318063; hg19: chr21-47721985; COSMIC: COSV52449901; COSMIC: COSV52449901;