1-244835738-T-G

Variant names:

• chr1-244835738-T-G
• rs915488593
• NM_198076.6:c.24T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001312873.1(COX20):​c.22+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000891 in 1,121,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 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: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: COX20 NM_001312873.1 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 0 publications found

Genes affected

COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

COX20 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex IV deficiency, nuclear type 11

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.1756756 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.2, offset of 20, new splice context is: aagGTaacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001312873.1. 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
	COX20	NM_198076.6	MANE Select	c.24T>G	p.Gly8Gly	synonymous	Exon 1 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.24T>G	p.Gly8Gly	synonymous	Exon 1 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.24T>G	p.Gly8Gly	synonymous	Exon 2 of 5	NP_001299800.1	Q5RI15-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	ENST00000411948.7	TSL:1 MANE Select	c.24T>G	p.Gly8Gly	synonymous	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.83T>G		non_coding_transcript_exon	Exon 1 of 3
	COX20	ENST00000366528.3	TSL:2	c.24T>G	p.Gly8Gly	synonymous	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.91e-7 AC: 1 AN: 1121978 Hom.: 0 Cov.: 31 AF XY: 0.00000186 AC XY: 1 AN XY: 537504

African (AFR) AF: 0.00 AC: 0 AN: 23708

American (AMR) AF: 0.00 AC: 0 AN: 11778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15902

East Asian (EAS) AF: 0.00 AC: 0 AN: 26932

South Asian (SAS) AF: 0.00 AC: 0 AN: 31052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3592

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 938390

Other (OTH) AF: 0.00 AC: 0 AN: 45170

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.58
PhyloP100		-1.5
PromoterAI		-0.097	Neutral
Mutation Taster		=100/0	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: rs915488593; hg19: chr1-244999040;