rs4964059

Positions:

• chr12-27376286-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020183.6(BMAL2):​c.285-60A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,435,296 control chromosomes in the GnomAD database, including 90,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.30 (7435 hom., cov: 32)
  • Exomes 𝑓: 0.35 (82590 hom.)
• Consequence: BMAL2 NM_020183.6 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.496

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMAL2	NM_020183.6	c.285-60A>C		intron_variant		ENST00000266503.10	NP_064568.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMAL2	ENST00000266503.10	c.285-60A>C		intron_variant		1	NM_020183.6	ENSP00000266503	P2

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44904 AN: 151988 Hom.: 7429 Cov.: 32

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.352 AC: 451635 AN: 1283190 Hom.: 82590 AF XY: 0.352 AC XY: 227795 AN XY: 646886

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.449

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.295 AC: 44934 AN: 152106 Hom.: 7435 Cov.: 32 AF XY: 0.297 AC XY: 22102 AN XY: 74366

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.293

Alfa AF: 0.341 Hom.: 19001

Bravo AF: 0.273

Asia WGS AF: 0.381 AC: 1324 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary disease, chronic obstructive, susceptibility to Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 10, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.72

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: rs4964059; hg19: chr12-27529219;