12-27376286-A-C

Variant names:

• chr12-27376286-A-C
• rs4964059
• NM_020183.6:c.285-60A>C

Variant summary

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

The NM_001394524.1(BMAL2):​c.318-60A>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_001394524.1 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.496
• Publications: 16 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: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394524.1. 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.285-60A>C		intron	N/A	NP_064568.3
	BMAL2	NM_001394524.1		c.318-60A>C		intron	N/A	NP_001381453.1
	BMAL2	NM_001394525.1		c.318-3961A>C		intron	N/A	NP_001381454.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL2	ENST00000266503.10	TSL:1 MANE Select	c.285-60A>C		intron	N/A	ENSP00000266503.5
	BMAL2	ENST00000311001.9	TSL:1	c.285-3961A>C		intron	N/A	ENSP00000312247.5
	BMAL2	ENST00000395901.6	TSL:1	c.216-3961A>C		intron	N/A	ENSP00000379238.2

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

African (AFR) AF: 0.159 AC: 4699 AN: 29536

American (AMR) AF: 0.174 AC: 7527 AN: 43158

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 5736 AN: 24448

East Asian (EAS) AF: 0.449 AC: 17396 AN: 38762

South Asian (SAS) AF: 0.314 AC: 25294 AN: 80434

European-Finnish (FIN) AF: 0.411 AC: 21725 AN: 52806

Middle Eastern (MID) AF: 0.190 AC: 1027 AN: 5394

European-Non Finnish (NFE) AF: 0.367 AC: 350138 AN: 954350

Other (OTH) AF: 0.333 AC: 18093 AN: 54302

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

African (AFR) AF: 0.165 AC: 6830 AN: 41516

American (AMR) AF: 0.213 AC: 3255 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3468

East Asian (EAS) AF: 0.447 AC: 2307 AN: 5164

South Asian (SAS) AF: 0.309 AC: 1486 AN: 4814

European-Finnish (FIN) AF: 0.416 AC: 4400 AN: 10568

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24894 AN: 67988

Other (OTH) AF: 0.293 AC: 618 AN: 2112

Alfa AF: 0.339 Hom.: 37280

Bravo AF: 0.273

Asia WGS AF: 0.381 AC: 1324 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Pulmonary disease, chronic obstructive, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.72
PhyloP100		-0.50
Mutation Taster		=100/0	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: rs4964059; hg19: chr12-27529219;