NM_207335.4:c.564A>G

Variant names:

• chr3-127923625-A-G
• rs779298064
• NM_207335.4:c.564A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_207335.4(KBTBD12):​c.564A>G​(p.Ile188Met) 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 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KBTBD12 NM_207335.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.151
• 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 2 ACMG points.

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

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.564A>G	p.Ile188Met	missense	Exon 2 of 6	NP_997218.2	Q3ZCT8-1
	KBTBD12	NM_001370224.1		c.564A>G	p.Ile188Met	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.564A>G	p.Ile188Met	missense	Exon 2 of 6	ENSP00000385957.1	Q3ZCT8-1
	KBTBD12	ENST00000407609.7	TSL:1	c.-109-4139A>G		intron	N/A	ENSP00000385830.3	B5MCZ4
	KBTBD12	ENST00000497045.1	TSL:1	n.565A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248484 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461382 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111738

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.15
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.63	P
Vest4		0.32
MutPred		0.72		Gain of glycosylation at S193 (P = 0.0197)
MVP		0.42
MPC		0.26
ClinPred		0.57	D
GERP RS		-12
PromoterAI		0.0072	Neutral
Varity_R		0.21
gMVP		0.42
Mutation Taster		=95/5	polymorphism

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: rs779298064; hg19: chr3-127642468;