12-27390155-A-G

Variant names:

• chr12-27390155-A-G
• NM_020183.6:c.835A>G

Variant summary

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

The NM_020183.6(BMAL2):​c.835A>G​(p.Arg279Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

BMAL2 (HGNC:18984): (basic helix-loop-helix ARNT like 2) This gene encodes a basic helix-loop-helix transcription factor belonging to the PAS (PER, ARNT, SIM) superfamily. The PAS proteins play important roles in adaptation to low atmospheric and cellular oxygen levels, exposure to certain environmental pollutants, and diurnal oscillations in light and temperature. This protein forms a transcriptionally active heterodimer with the circadian CLOCK protein, the structurally related MOP4, and hypoxia-inducible factors, such as HIF1alpha. Consistent with its role as a biologically relevant partner of circadian and hypoxia factors, this protein is coexpressed in regions of the brain such as the thalamus, hypothalamus, and amygdala. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

BMAL2-AS1 (HGNC:49892): (BMAL2 antisense RNA 1)

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 rank	MANE	Protein	UniProt
BMAL2	NM_020183.6	c.835A>G	p.Arg279Gly	missense_variant	Exon 9 of 17	ENST00000266503.10	NP_064568.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMAL2	ENST00000266503.10	c.835A>G	p.Arg279Gly	missense_variant	Exon 9 of 17	1	NM_020183.6	ENSP00000266503.5
BMAL2	ENST00000457040.6	c.688A>G	p.Arg230Gly	missense_variant	Exon 7 of 15	1		ENSP00000400185.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.835A>G (p.R279G) alteration is located in exon 9 (coding exon 9) of the ARNTL2 gene. This alteration results from a A to G substitution at nucleotide position 835, causing the arginine (R) at amino acid position 279 to be replaced by a glycine (G). 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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;.;.;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Benign	0.0060	T
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;.
Vest4		0.57
MutPred		0.68		.;.;.;.;.;Gain of catalytic residue at S278 (P = 0);.;
MVP		0.37
MPC		0.62
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.73
gMVP		0.81

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: chr12-27543088;