Genetic Variant CLYBL:p.Arg11Cys (chr13-99606726-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_206808.5(CLYBL):c.31C>T(p.Arg11Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,490,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R11G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CLYBL
NM_206808.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.818

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:

ENSG00000307597 (HGNC:):

ENSG00000307597 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008576959).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5 link	c.31C>T	p.Arg11Cys	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.31C>T	p.Arg11Cys	missense_variant	Exon 1 of 9	1	NM_206808.5	ENSP00000342991.4		Q8N0X4-1

Frequencies

GnomAD3 genomes

AF:

0.000818

AC:

124

AN:

151596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000109

AC:

AN:

100508

AF XY:

0.000106

show subpopulations

Gnomad AFR exome

AF:

0.00368

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:

0.0000499

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000209

AC:

280

AN:

1338644

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

142

AN XY:

660684

show subpopulations

African (AFR)

AF:

0.00380

AC:

103

AN:

27134

American (AMR)

AF:

0.0000993

AC:

AN:

30218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23548

East Asian (EAS)

AF:

0.00

AC:

AN:

29686

South Asian (SAS)

AF:

0.0000814

AC:

AN:

73742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4156

European-Non Finnish (NFE)

AF:

0.000150

AC:

159

AN:

1058422

Other (OTH)

AF:

0.000162

AC:

AN:

55630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000817

AC:

124

AN:

151706

Hom.:

Cov.:

AF XY:

0.000876

AC XY:

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.00281

AC:

116

AN:

41226

American (AMR)

AF:

0.000394

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000490

Hom.:

Bravo

AF:

0.000997

ESP6500AA

AF:

0.00218

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000143

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

T;.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.68

.;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.0086

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

0.82

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.30

MVP

0.43

ClinPred

0.10

GERP RS

3.5

PromoterAI

0.078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.20

gMVP

0.49

Mutation Taster

=87/13

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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13-99606726-C-T

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