12-27400633-A-G

Position:

• chr12-27400633-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMAL2	NM_020183.6	c.1019A>G	p.Asn340Ser	missense_variant	10/17	ENST00000266503.10	NP_064568.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMAL2	ENST00000266503.10	c.1019A>G	p.Asn340Ser	missense_variant	10/17	1	NM_020183.6	ENSP00000266503.5
BMAL2	ENST00000457040.6	c.872A>G	p.Asn291Ser	missense_variant	8/15	1		ENSP00000400185.2

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

GnomAD3 exomes AF: 0.0456 AC: 11471 AN: 251336 Hom.: 343 AF XY: 0.0488 AC XY: 6625 AN XY: 135822

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 SAS exome AF: 0.0781

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

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.0200

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0819

Gnomad4 FIN exome AF: 0.0793

Gnomad4 NFE exome AF: 0.0504

Gnomad4 OTH exome AF: 0.0465

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

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0713

Gnomad4 FIN AF: 0.0787

Gnomad4 NFE AF: 0.0492

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0442 Hom.: 405

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 v4.3

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;T;T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	.;.;.;.;.;N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.6	N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;B;.
Vest4		0.019
MPC		0.087
ClinPred		0.0041	T
GERP RS		0.40
Varity_R		0.022
gMVP		0.13

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

LitVar

Other links and lift over

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