NM_207335.4:c.646C>A

Variant names:

• chr3-127923707-C-A
• rs1939487298
• NM_207335.4:c.646C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_207335.4(KBTBD12):​c.646C>A​(p.Leu216Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L216V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KBTBD12 NM_207335.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86
• Publications: 0 publications found

Genes affected

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

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207335.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD12	NM_207335.4	MANE Select	c.646C>A	p.Leu216Ile	missense	Exon 2 of 6	NP_997218.2	Q3ZCT8-1
	KBTBD12	NM_001370224.1		c.646C>A	p.Leu216Ile	missense	Exon 2 of 7	NP_001357153.1	Q3ZCT8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD12	ENST00000405109.5	TSL:5 MANE Select	c.646C>A	p.Leu216Ile	missense	Exon 2 of 6	ENSP00000385957.1	Q3ZCT8-1
	KBTBD12	ENST00000407609.7	TSL:1	c.-109-4057C>A		intron	N/A	ENSP00000385830.3	B5MCZ4
	KBTBD12	ENST00000497045.1	TSL:1	n.647C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.45
Sift	Benign	0.030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.70		Gain of ubiquitination at K218 (P = 0.072)
MVP		0.75
MPC		0.32
ClinPred		0.83	D
GERP RS		5.9
PromoterAI		-0.0054	Neutral
Varity_R		0.18
gMVP		0.42
Mutation Taster		=19/81	disease causing

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

Other links and lift over

dbSNP: rs1939487298; hg19: chr3-127642550;