3-127923083-A-G

Position:

• chr3-127923083-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207335.4(KBTBD12):​c.22A>G​(p.Lys8Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KBTBD12 NM_207335.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

Genes affected

KBTBD12 (HGNC:25731): (kelch repeat and BTB domain containing 12)

KBTBD12 (HGNC:):

MGLL (HGNC:17038): (monoglyceride lipase) This gene encodes a serine hydrolase of the AB hydrolase superfamily that catalyzes the conversion of monoacylglycerides to free fatty acids and glycerol. The encoded protein plays a critical role in several physiological processes including pain and nociperception through hydrolysis of the endocannabinoid 2-arachidonoylglycerol. Expression of this gene may play a role in cancer tumorigenesis and metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09336808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD12	NM_207335.4	c.22A>G	p.Lys8Glu	missense_variant	2/6	ENST00000405109.5	NP_997218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD12	ENST00000405109.5	c.22A>G	p.Lys8Glu	missense_variant	2/6	5	NM_207335.4	ENSP00000385957.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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

Jan 03, 2024

The c.22A>G (p.K8E) alteration is located in exon 1 (coding exon 1) of the KBTBD12 gene. This alteration results from a A to G substitution at nucleotide position 22, causing the lysine (K) at amino acid position 8 to be replaced by a glutamic acid (E). 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	0.076
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0092	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.15
Sift	Benign	0.14	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0060	B;B
Vest4		0.20
MutPred		0.39		Loss of methylation at K8 (P = 0.0127);Loss of methylation at K8 (P = 0.0127);
MVP		0.37
MPC		0.056
ClinPred		0.21	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-127641926;