13-99858871-G-C

Variant names:

• chr13-99858871-G-C
• rs1440832118
• NM_206808.5:c.260G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_206808.5(CLYBL):​c.260G>C​(p.Arg87Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CLYBL NM_206808.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.41
• Publications: 0 publications found

Genes affected

CLYBL (HGNC:18355): (citramalyl-CoA lyase) Enables (S)-citramalyl-CoA lyase activity; magnesium ion binding activity; and malate synthase activity. Involved in protein homotrimerization and regulation of cobalamin metabolic process. Predicted to be located in mitochondrion. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286757 (HGNC:):

CLYBL-AS3 (HGNC:56191): (CLYBL antisense RNA 3)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5	c.260G>C	p.Arg87Pro	missense_variant	Exon 3 of 9	ENST00000339105.9	NP_996531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLYBL	ENST00000339105.9	c.260G>C	p.Arg87Pro	missense_variant	Exon 3 of 9	1	NM_206808.5	ENSP00000342991.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448616 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720014

African (AFR) AF: 0.00 AC: 0 AN: 32676

American (AMR) AF: 0.00 AC: 0 AN: 41644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 83366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107254

Other (OTH) AF: 0.00 AC: 0 AN: 59768

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;.
PhyloP100		9.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.94
MutPred		0.79		Gain of ubiquitination at K83 (P = 0.0544);Gain of ubiquitination at K83 (P = 0.0544);Gain of ubiquitination at K83 (P = 0.0544);.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		0.0054	Neutral
Varity_R		0.99
gMVP		0.95
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs1440832118; hg19: chr13-100511125;