13-99606705-C-A

Variant names:

• chr13-99606705-C-A
• rs865840508
• NM_206808.5:c.10C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206808.5(CLYBL):​c.10C>A​(p.Arg4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000536 in 1,492,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: CLYBL NM_206808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0450
• 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]

ENSG00000307597 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087581426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5	c.10C>A	p.Arg4Ser	missense_variant	Exon 1 of 9	ENST00000339105.9	NP_996531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLYBL	ENST00000339105.9	c.10C>A	p.Arg4Ser	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151686 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000448 AC: 6 AN: 1340742 Hom.: 0 Cov.: 35 AF XY: 0.00000907 AC XY: 6 AN XY: 661742

African (AFR) AF: 0.0000366 AC: 1 AN: 27316

American (AMR) AF: 0.00 AC: 0 AN: 30748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23572

East Asian (EAS) AF: 0.00 AC: 0 AN: 29866

South Asian (SAS) AF: 0.0000406 AC: 3 AN: 73880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4188

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1059590

Other (OTH) AF: 0.00 AC: 0 AN: 55730

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151686 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74072

African (AFR) AF: 0.0000242 AC: 1 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10C>A (p.R4S) alteration is located in exon 1 (coding exon 1) of the CLYBL gene. This alteration results from a C to A substitution at nucleotide position 10, causing the arginine (R) at amino acid position 4 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.052	T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.47	.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;L;L
PhyloP100		-0.045
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.36	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.55	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.039	B;B;B
Vest4		0.44
MutPred		0.26		Loss of methylation at R4 (P = 0.0143);Loss of methylation at R4 (P = 0.0143);Loss of methylation at R4 (P = 0.0143);
MVP		0.23
ClinPred		0.13	T
GERP RS		0.69
PromoterAI		-0.33	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.53
Mutation Taster		=91/9	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: rs865840508; hg19: chr13-100258959;