Genetic Variant C21orf58:p.His299del (chr21-46302071-ATGG-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3BS1BS2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.512

Publications

12 publications found

Variant links:

Genes affected

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

C21orf58 links:

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]

YBEY links:

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ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C21orf58	NM_058180.5 link	c.894_896delCCA	p.His299del	disruptive_inframe_deletion	Exon 8 of 8	ENST00000291691.12	NP_478060.2	P58505-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C21orf58	ENST00000291691.12 link	c.894_896delCCA	p.His299del	disruptive_inframe_deletion	Exon 8 of 8	2	NM_058180.5	ENSP00000291691.8		P58505-1

Frequencies

GnomAD3 genomes

AF:

0.00574

AC:

869

AN:

151402

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00112

AC XY:

745

AN XY:

663956

show subpopulations

⚠️ 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:

AN:

32124

Ashkenazi Jewish (ASJ)

AF:

0.000994

AC:

AN:

24146

East Asian (EAS)

AF:

0.000648

AC:

AN:

33958

South Asian (SAS)

AF:

0.000892

AC:

AN:

75154

European-Finnish (FIN)

AF:

0.000980

AC:

AN:

41822

Middle Eastern (MID)

AF:

0.00165

AC:

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00575

AC:

871

AN:

151518

Hom.:

Cov.:

AF XY:

0.00551

AC XY:

408

AN XY:

74000

show subpopulations

African (AFR)

AF:

0.0197

AC:

815

AN:

41384

American (AMR)

AF:

0.00210

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.000418

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67750

Other (OTH)

AF:

0.00478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00380

Hom.:

491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.51

Mutation Taster

=85/15

polymorphism

(source)

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

Publications

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chr21-46302071-ATGG-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over