Genetic Variant CLYBL:p.Ala16Gly (chr13-99606742-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_206808.5(CLYBL):c.47C>G(p.Ala16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,482,594 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. 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. A16V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CLYBL
NM_206808.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0540

Publications

0 publications found

Variant links:

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]

CLYBL links:

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ACMG classification

Classification was made for transcript

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=0.018506259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5 link	c.47C>G	p.Ala16Gly	missense_variant	Exon 1 of 9	ENST00000339105.9	NP_996531.1	Q8N0X4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLYBL	ENST00000339105.9 link	c.47C>G	p.Ala16Gly	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4		Q8N0X4-1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000183

AC:

AN:

93040

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000278

Gnomad OTH exome

AF:

0.000774

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1331504

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

656922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26934

American (AMR)

AF:

0.00

AC:

AN:

29188

Ashkenazi Jewish (ASJ)

AF:

0.00167

AC:

AN:

23414

East Asian (EAS)

AF:

0.00

AC:

AN:

29324

South Asian (SAS)

AF:

0.0000137

AC:

AN:

73108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4050

European-Non Finnish (NFE)

AF:

0.00000759

AC:

AN:

1054396

Other (OTH)

AF:

0.0000543

AC:

AN:

55276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151090

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73804

show subpopulations

African (AFR)

AF:

0.0000489

AC:

AN:

40874

American (AMR)

AF:

0.00

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67836

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000330

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000642

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.069

T;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.53

.;T;T

M_CAP

Benign

0.0087

MetaRNN

Benign

0.019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L

PhyloP100

0.054

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.33

N;N;N

REVEL

Benign

0.020

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.19

B;B;B

Vest4

0.37

MutPred

0.43

Gain of catalytic residue at A16 (P = 0);Gain of catalytic residue at A16 (P = 0);Gain of catalytic residue at A16 (P = 0);

MVP

0.13

ClinPred

0.11

GERP RS

1.6

PromoterAI

-0.39

Neutral

(source)

Varity_R

0.042

gMVP

0.46

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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13-99606742-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over