Variant 5-10286403-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138809.4(CMBL):c.417T>G(p.His139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CMBL
NM_138809.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.403

Variant links:

Genes affected

CMBL (HGNC:25090): (carboxymethylenebutenolidase homolog) CMBL (EC 3.1.1.45) is a cysteine hydrolase of the dienelactone hydrolase family that is highly expressed in liver cytosol. CMBL preferentially cleaves cyclic esters, and it activates medoxomil-ester prodrugs in which the medoxomil moiety is linked to an oxygen atom (Ishizuka et al., 2010 [PubMed 20177059]).[supplied by OMIM, Apr 2010]

CMBL links:

CMBL (HGNC:):

CMBL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30949718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMBL	NM_138809.4 linkuse as main transcript	c.417T>G	p.His139Gln	missense_variant	4/6	ENST00000296658.4	NP_620164.1	Q96DG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CMBL	ENST00000296658.4 linkuse as main transcript	c.417T>G	p.His139Gln	missense_variant	4/6	1	NM_138809.4	ENSP00000296658.3	Q96DG6
CMBL	ENST00000506821.1 linkuse as main transcript	n.671T>G		non_coding_transcript_exon_variant	4/4	2
CMBL	ENST00000510532.5 linkuse as main transcript	n.485T>G		non_coding_transcript_exon_variant	4/5	3
CMBL	ENST00000511963.5 linkuse as main transcript	n.525T>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251452

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.417T>G (p.H139Q) alteration is located in exon 4 (coding exon 3) of the CMBL gene. This alteration results from a T to G substitution at nucleotide position 417, causing the histidine (H) at amino acid position 139 to be replaced by a glutamine (Q). 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.73

M_CAP

Benign

0.0067

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

REVEL

Benign

0.18

Sift

Benign

0.35

Sift4G

Benign

0.35

Polyphen

0.64

Vest4

0.41

MutPred

0.55

Loss of catalytic residue at L141 (P = 0.0816);

MVP

0.47

MPC

0.10

ClinPred

0.56

GERP RS

0.21

Varity_R

0.28

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over