12-27385489-A-G

Variant names:

• chr12-27385489-A-G
• rs145846813
• NM_020183.6:c.493A>G

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.493A>G​(p.Asn165Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000289 in 1,453,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23
• Publications: 1 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]

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=0.14855528).

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.493A>G	p.Asn165Asp	missense	Exon 6 of 17	NP_064568.3
	BMAL2	NM_001394524.1		c.526A>G	p.Asn176Asp	missense	Exon 6 of 17	NP_001381453.1
	BMAL2	NM_001394525.1		c.484A>G	p.Asn162Asp	missense	Exon 5 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.493A>G	p.Asn165Asp	missense	Exon 6 of 17	ENSP00000266503.5	Q8WYA1-1
	BMAL2	ENST00000311001.9	TSL:1	c.451A>G	p.Asn151Asp	missense	Exon 5 of 16	ENSP00000312247.5	Q8WYA1-2
	BMAL2	ENST00000395901.6	TSL:1	c.382A>G	p.Asn128Asp	missense	Exon 4 of 15	ENSP00000379238.2	Q8WYA1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249924 AF XY: 0.00000740

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 42 AN: 1453410 Hom.: 0 Cov.: 28 AF XY: 0.0000235 AC XY: 17 AN XY: 723672

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000380 AC: 42 AN: 1105040

Other (OTH) AF: 0.00 AC: 0 AN: 60094

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

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	0.075
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.099
Sift	Uncertain	0.025	D
Sift4G	Benign	0.34	T
Polyphen		0.029	B
Vest4		0.13
MVP		0.33
MPC		0.13
ClinPred		0.23	T
GERP RS		1.3
Varity_R		0.082
gMVP		0.20
Mutation Taster		=93/7	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: rs145846813; hg19: chr12-27538422;