5-10286448-C-A

Position:

• chr5-10286448-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138809.4(CMBL):​c.372G>T​(p.Gln124His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CMBL NM_138809.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMBL	NM_138809.4	c.372G>T	p.Gln124His	missense_variant	4/6	ENST00000296658.4	NP_620164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMBL	ENST00000296658.4	c.372G>T	p.Gln124His	missense_variant	4/6	1	NM_138809.4	ENSP00000296658.3
CMBL	ENST00000506821.1	n.626G>T		non_coding_transcript_exon_variant	4/4	2
CMBL	ENST00000510532.5	n.440G>T		non_coding_transcript_exon_variant	4/5	3
CMBL	ENST00000511963.5	n.480G>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.372G>T (p.Q124H) alteration is located in exon 4 (coding exon 3) of the CMBL gene. This alteration results from a G to T substitution at nucleotide position 372, causing the glutamine (Q) at amino acid position 124 to be replaced by a histidine (H). 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	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.068
Sift	Uncertain	0.017	D
Sift4G	Benign	0.067	T
Polyphen		0.79	P
Vest4		0.27
MutPred		0.37		Loss of catalytic residue at Q124 (P = 0.0679);
MVP		0.69
MPC		0.13
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.34
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 48

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-10286560;