22-50526102-ACCAGCG-ACCAGCGCCAGCG

Variant names:

• chr22-50526102-A-ACCAGCG
• rs786205098
• NM_001953.5:c.1193_1198dupCGCTGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The ENST00000252029.8(TYMP):​c.1193_1198dupCGCTGG​(p.Ala398_Leu399dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V400V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TYMP ENST00000252029.8 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 0 publications found

Genes affected

TYMP (HGNC:3148): (thymidine phosphorylase) This gene encodes an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. It has a highly restricted target cell specificity acting only on endothelial cells. Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Apr 2012]

SCO2 (HGNC:10604): (synthesis of cytochrome C oxidase 2) Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6. [provided by RefSeq, Oct 2014]

SCO2 Gene-Disease associations (from GenCC):

• cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopia 6

  Inheritance: AD Classification: STRONG Submitted by: G2P
• autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in ENST00000252029.8

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252029.8. 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
	TYMP	NM_001953.5	MANE Select	c.1193_1198dupCGCTGG	p.Ala398_Leu399dup	conservative_inframe_insertion	Exon 9 of 10	NP_001944.1
	TYMP	NM_001257989.1		c.1208_1213dupCGCTGG	p.Ala403_Leu404dup	conservative_inframe_insertion	Exon 9 of 10	NP_001244918.1
	TYMP	NM_001113755.3		c.1193_1198dupCGCTGG	p.Ala398_Leu399dup	conservative_inframe_insertion	Exon 9 of 10	NP_001107227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1193_1198dupCGCTGG	p.Ala398_Leu399dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000252029.3
	TYMP	ENST00000395681.6	TSL:1	c.1208_1213dupCGCTGG	p.Ala403_Leu404dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000379038.1
	TYMP	ENST00000395678.7	TSL:1	c.1193_1198dupCGCTGG	p.Ala398_Leu399dup	conservative_inframe_insertion	Exon 9 of 10	ENSP00000379036.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

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

Other links and lift over

dbSNP: rs786205098; hg19: chr22-50964531;