Genetic Variant NM_206808.5:c.5C>A (chr13-99606700-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_206808.5(CLYBL):c.5C>A(p.Ala2Glu) 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 1,490,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A2G) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Publications

1 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:

ENSG00000307597 (HGNC:):

ENSG00000307597 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5 link	c.5C>A	p.Ala2Glu	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.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4		Q8N0X4-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151662

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00000299

AC:

AN:

1338642

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

660684

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27282

American (AMR)

AF:

0.0000327

AC:

AN:

30548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23516

East Asian (EAS)

AF:

0.00

AC:

AN:

29764

South Asian (SAS)

AF:

0.00

AC:

AN:

73750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4172

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1058344

Other (OTH)

AF:

0.00

AC:

AN:

55638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41248

American (AMR)

AF:

0.00

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.075

T;.;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.49

.;T;T

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

1.5

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.074

T;T;T

Sift4G

Benign

0.10

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.55

MutPred

0.32

Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);

MVP

0.53

ClinPred

0.93

GERP RS

3.5

PromoterAI

-0.68

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.19

gMVP

0.88

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

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NM_206808.5:c.5C>A

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