13-99606708-C-G

Variant names:

• chr13-99606708-C-G
• rs570970577
• NM_206808.5:c.13C>G

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.13C>G​(p.Leu5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,494,398 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: CLYBL NM_206808.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.366
• 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=0.04741153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5	c.13C>G	p.Leu5Val	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.13C>G	p.Leu5Val	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151922 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 104862 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000596 AC: 8 AN: 1342368 Hom.: 0 Cov.: 35 AF XY: 0.00000453 AC XY: 3 AN XY: 662542

African (AFR) AF: 0.000220 AC: 6 AN: 27330

American (AMR) AF: 0.00 AC: 0 AN: 30894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23610

East Asian (EAS) AF: 0.00 AC: 0 AN: 29958

South Asian (SAS) AF: 0.00 AC: 0 AN: 74012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4208

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060522

Other (OTH) AF: 0.0000179 AC: 1 AN: 55820

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152030 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.000145 AC: 6 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000198 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13C>G (p.L5V) alteration is located in exon 1 (coding exon 1) of the CLYBL gene. This alteration results from a C to G substitution at nucleotide position 13, causing the leucine (L) at amino acid position 5 to be replaced by a valine (V). 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	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.085	T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.46	.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;L;L
PhyloP100		0.37
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.015
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.34
MutPred		0.31		Gain of methylation at R8 (P = 0.1233);Gain of methylation at R8 (P = 0.1233);Gain of methylation at R8 (P = 0.1233);
MVP		0.055
ClinPred		0.15	T
GERP RS		1.6
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.048
gMVP		0.51
Mutation Taster		=99/1	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: rs570970577; hg19: chr13-100258962;