rs35878285

Positions:

• chr12-27403456-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020183.6(BMAL2):​c.1501A>G​(p.Ser501Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,607,840 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0023 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064353943).
• BS2: High Homozygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMAL2	NM_020183.6	c.1501A>G	p.Ser501Gly	missense_variant	14/17	ENST00000266503.10
BMAL2-AS1	NR_109975.1	n.139-8833T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMAL2	ENST00000266503.10	c.1501A>G	p.Ser501Gly	missense_variant	14/17	1	NM_020183.6	P2
BMAL2-AS1	ENST00000500498.2	n.130-8833T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152234 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00198 AC: 494 AN: 250098 Hom.: 1 AF XY: 0.00197 AC XY: 267 AN XY: 135242

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00325 AC: 4732 AN: 1455488 Hom.: 12 Cov.: 28 AF XY: 0.00316 AC XY: 2288 AN XY: 724476

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00279

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152352 Hom.: 1 Cov.: 31 AF XY: 0.00211 AC XY: 157 AN XY: 74504

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00309 Hom.: 1

Bravo AF: 0.00224

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00185 AC: 225

EpiCase AF: 0.00313

EpiControl AF: 0.00315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.89
DEOGEN2	Benign	0.0046	.;.;.;.;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T;T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	.;.;.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.16	T;T;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T;T
Polyphen		0.0070	B;B;.;B;B;B;.
Vest4		0.091
MVP		0.25
MPC		0.10
ClinPred		0.0031	T
GERP RS		0.12
Varity_R		0.040
gMVP		0.15

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: rs35878285; hg19: chr12-27556389;