rs140404198

Variant names:

• chr12-27368390-G-A
• rs140404198
• NM_020183.6:c.160G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020183.6(BMAL2):​c.160G>A​(p.Gly54Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045532227).

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.160G>A	p.Gly54Arg	missense	Exon 2 of 17	NP_064568.3
	BMAL2	NM_001394524.1		c.193G>A	p.Gly65Arg	missense	Exon 2 of 17	NP_001381453.1
	BMAL2	NM_001394525.1		c.193G>A	p.Gly65Arg	missense	Exon 2 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.160G>A	p.Gly54Arg	missense	Exon 2 of 17	ENSP00000266503.5	Q8WYA1-1
	BMAL2	ENST00000311001.9	TSL:1	c.160G>A	p.Gly54Arg	missense	Exon 2 of 16	ENSP00000312247.5	Q8WYA1-2
	BMAL2	ENST00000395901.6	TSL:1	c.193G>A	p.Gly65Arg	missense	Exon 2 of 15	ENSP00000379238.2	Q8WYA1-3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 20 AN: 251428 AF XY: 0.0000957

Gnomad AFR exome AF: 0.0000615

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: 0.000149

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461866 Hom.: 0 Cov.: 30 AF XY: 0.000160 AC XY: 116 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000235 AC: 261 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

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	0.28
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.95	L
PhyloP100		1.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.057
Sift	Benign	0.052	T
Sift4G	Benign	0.57	T
Polyphen		0.010	B
Vest4		0.16
MutPred		0.32		Gain of catalytic residue at P59 (P = 0.0059)
MVP		0.19
MPC		0.14
ClinPred		0.061	T
GERP RS		1.5
PromoterAI		-0.048	Neutral
Varity_R		0.047
gMVP		0.23
Mutation Taster		=69/31	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: rs140404198; hg19: chr12-27521323;