2-98604134-C-G

Position:

• chr2-98604134-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001008215.3(COA5):​c.157G>C​(p.Ala53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COA5 NM_001008215.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.952

Genes affected

COA5 (HGNC:33848): (cytochrome c oxidase assembly factor 5) This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency, a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to a severe disease affecting several tissues and organs. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-98604134-C-G is Pathogenic according to our data. Variant chr2-98604134-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 31087.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-98604134-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COA5	NM_001008215.3	c.157G>C	p.Ala53Pro	missense_variant	2/3	ENST00000328709.8	NP_001008216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COA5	ENST00000328709.8	c.157G>C	p.Ala53Pro	missense_variant	2/3	1	NM_001008215.3	ENSP00000330730.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461318 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 08, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.94	D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.52	T
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.58
Sift	Benign	0.079	T;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.96	D;.
Vest4		0.46
MutPred		0.62		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);
MVP		0.53
MPC		0.28
ClinPred		0.73	D
GERP RS		3.0
Varity_R		0.80
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907099; hg19: chr2-99220597;