13-99606733-C-A

Variant names:

• chr13-99606733-C-A
• rs759290602
• NM_206808.5:c.38C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_206808.5(CLYBL):​c.38C>A​(p.Ala13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000336 in 1,487,638 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. A13V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CLYBL NM_206808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.733
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03382173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5	c.38C>A	p.Ala13Asp	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.38C>A	p.Ala13Asp	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151406 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000508 AC: 5 AN: 98370 AF XY: 0.0000361

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1336122 Hom.: 0 Cov.: 35 AF XY: 0.00000303 AC XY: 2 AN XY: 659328

African (AFR) AF: 0.00 AC: 0 AN: 27056

American (AMR) AF: 0.00 AC: 0 AN: 29788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23500

East Asian (EAS) AF: 0.000135 AC: 4 AN: 29566

South Asian (SAS) AF: 0.00 AC: 0 AN: 73330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057204

Other (OTH) AF: 0.00 AC: 0 AN: 55512

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151516 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74094

African (AFR) AF: 0.00 AC: 0 AN: 41138

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>A (p.A13D) 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 38, causing the alanine (A) at amino acid position 13 to be replaced by an aspartic acid (D). 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	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.47	.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		-0.73
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.040	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.077	B;B;B
Vest4		0.40
MutPred		0.37		Gain of catalytic residue at G12 (P = 0.0254);Gain of catalytic residue at G12 (P = 0.0254);Gain of catalytic residue at G12 (P = 0.0254);
MVP		0.14
ClinPred		0.053	T
GERP RS		0.35
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.62
Mutation Taster		=94/6	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: rs759290602; hg19: chr13-100258987;