chr12-27400611-G-C

Variant names:

• chr12-27400611-G-C
• rs1162131504
• NM_020183.6:c.997G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020183.6(BMAL2):​c.997G>C​(p.Glu333Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.55
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18577579).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020183.6. 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
	BMAL2	NM_020183.6	MANE Select	c.997G>C	p.Glu333Gln	missense	Exon 10 of 17	NP_064568.3
	BMAL2	NM_001394524.1		c.1030G>C	p.Glu344Gln	missense	Exon 10 of 17	NP_001381453.1
	BMAL2	NM_001394525.1		c.988G>C	p.Glu330Gln	missense	Exon 9 of 16	NP_001381454.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL2	ENST00000266503.10	TSL:1 MANE Select	c.997G>C	p.Glu333Gln	missense	Exon 10 of 17	ENSP00000266503.5	Q8WYA1-1
	BMAL2	ENST00000311001.9	TSL:1	c.955G>C	p.Glu319Gln	missense	Exon 9 of 16	ENSP00000312247.5	Q8WYA1-2
	BMAL2	ENST00000395901.6	TSL:1	c.886G>C	p.Glu296Gln	missense	Exon 8 of 15	ENSP00000379238.2	Q8WYA1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461584 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0037	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.96	D
Vest4		0.29
MutPred		0.43		Gain of catalytic residue at V328 (P = 0.0134)
MVP		0.51
MPC		0.49
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.50
Mutation Taster		=45/55	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: rs1162131504; hg19: chr12-27553544;