rs1558174241

Variant names:

• chr1-244835729-G-GGAGCCCGGTGAGCCC
• rs1558174241
• NM_198076.6:c.19_33dupCCCGGTGAGCCCGAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_198076.6(COX20):​c.19_33dupCCCGGTGAGCCCGAG​(p.Pro7_Glu11dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,118,438 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: COX20 NM_198076.6 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.82
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198076.6.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198076.6. 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.19_33dupCCCGGTGAGCCCGAG	p.Pro7_Glu11dup	conservative_inframe_insertion	Exon 1 of 4	NP_932342.1	Q5RI15-1
	COX20	NM_001312872.1		c.19_33dupCCCGGTGAGCCCGAG	p.Pro7_Glu11dup	conservative_inframe_insertion	Exon 1 of 5	NP_001299801.1	B3KM21
	COX20	NM_001312871.1		c.19_33dupCCCGGTGAGCCCGAG	p.Pro7_Glu11dup	conservative_inframe_insertion	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.19_33dupCCCGGTGAGCCCGAG	p.Pro7_Glu11dup	conservative_inframe_insertion	Exon 1 of 4	ENSP00000406327.2	Q5RI15-1
	COX20	ENST00000391839.6	TSL:1	n.78_92dupCCCGGTGAGCCCGAG		non_coding_transcript_exon	Exon 1 of 3
	COX20	ENST00000366528.3	TSL:2	c.19_33dupCCCGGTGAGCCCGAG	p.Pro7_Glu11dup	conservative_inframe_insertion	Exon 1 of 5	ENSP00000355486.3	Q5RI15-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1118438 Hom.: 0 Cov.: 31 AF XY: 0.00000373 AC XY: 2 AN XY: 535496

African (AFR) AF: 0.00 AC: 0 AN: 23562

American (AMR) AF: 0.00 AC: 0 AN: 11066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15730

East Asian (EAS) AF: 0.00 AC: 0 AN: 26926

South Asian (SAS) AF: 0.0000658 AC: 2 AN: 30408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3496

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937202

Other (OTH) AF: 0.00 AC: 0 AN: 44992

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1558174241; hg19: chr1-244999031;