Genetic Variant CLYBL:p.Ala2Gly (chr13-99606700-C-G) – 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>G(p.Ala2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,490,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CLYBL
NM_206808.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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>G	p.Ala2Gly	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>G	p.Ala2Gly	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4		Q8N0X4-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000967

AC:

AN:

103396

AF XY:

0.00

show subpopulations

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:

0.0000239

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

1338644

Hom.:

Cov.:

AF XY:

0.0000212

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:

23518

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:

0.000240

AC:

AN:

4172

European-Non Finnish (NFE)

AF:

0.0000217

AC:

AN:

1058344

Other (OTH)

AF:

0.00

AC:

AN:

55638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151662

Hom.:

Cov.:

AF XY:

0.0000135

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:

0.0000442

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000986

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5C>G (p.A2G) 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 5, causing the alanine (A) at amino acid position 2 to be replaced by a glycine (G). 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

0.12

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.074

T;.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.51

.;T;T

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;M;M

PhyloP100

1.5

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.42

MutPred

0.35

Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);

MVP

0.32

ClinPred

0.85

GERP RS

3.5

PromoterAI

-0.79

Under-expression

(source)

Varity_R

0.10

gMVP

0.78

Mutation Taster

=83/17

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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chr13-99606700-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over