12-27400633-A-G

Variant names:

• chr12-27400633-A-G
• rs1037921
• NM_020183.6:c.1019A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020183.6(BMAL2):​c.1019A>G​(p.Asn340Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0491 in 1,613,832 control chromosomes in the GnomAD database, including 2,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (147 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2147 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20
• Publications: 22 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017354488).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL2	NM_020183.6	MANE Select	c.1019A>G	p.Asn340Ser	missense	Exon 10 of 17	NP_064568.3
	BMAL2	NM_001394524.1		c.1052A>G	p.Asn351Ser	missense	Exon 10 of 17	NP_001381453.1
	BMAL2	NM_001394525.1		c.1010A>G	p.Asn337Ser	missense	Exon 9 of 16	NP_001381454.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL2	ENST00000266503.10	TSL:1 MANE Select	c.1019A>G	p.Asn340Ser	missense	Exon 10 of 17	ENSP00000266503.5
	BMAL2	ENST00000311001.9	TSL:1	c.977A>G	p.Asn326Ser	missense	Exon 9 of 16	ENSP00000312247.5
	BMAL2	ENST00000395901.6	TSL:1	c.908A>G	p.Asn303Ser	missense	Exon 8 of 15	ENSP00000379238.2

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6067 AN: 152200 Hom.: 147 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0708

Gnomad FIN AF: 0.0787

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0456 AC: 11471 AN: 251336 AF XY: 0.0488

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0796

Gnomad NFE exome AF: 0.0497

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0500 AC: 73138 AN: 1461514 Hom.: 2147 Cov.: 31 AF XY: 0.0512 AC XY: 37248 AN XY: 727076

African (AFR) AF: 0.0229 AC: 765 AN: 33472

American (AMR) AF: 0.0200 AC: 894 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 869 AN: 26124

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39648

South Asian (SAS) AF: 0.0819 AC: 7063 AN: 86232

European-Finnish (FIN) AF: 0.0793 AC: 4237 AN: 53412

Middle Eastern (MID) AF: 0.0727 AC: 419 AN: 5764

European-Non Finnish (NFE) AF: 0.0504 AC: 56076 AN: 1111772

Other (OTH) AF: 0.0465 AC: 2805 AN: 60374

GnomAD4 genome AF: 0.0398 AC: 6066 AN: 152318 Hom.: 147 Cov.: 33 AF XY: 0.0411 AC XY: 3062 AN XY: 74484

African (AFR) AF: 0.0221 AC: 918 AN: 41574

American (AMR) AF: 0.0240 AC: 368 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4828

European-Finnish (FIN) AF: 0.0787 AC: 835 AN: 10616

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3349 AN: 68018

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0437 Hom.: 559

Bravo AF: 0.0336

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0483 AC: 415

ExAC AF: 0.0471 AC: 5718

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.00061	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
PhyloP100		4.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.087
ClinPred		0.0041	T
GERP RS		0.40
Varity_R		0.022
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs1037921; hg19: chr12-27553566; COSMIC: COSV53825849;