Genetic Variant BMAL2:p.Lys559Glu (chr12-27418097-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020183.6(BMAL2):c.1675A>G(p.Lys559Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BMAL2
NM_020183.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.991

Publications

0 publications found

Variant links:

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 links:

BMAL2-AS1 (HGNC:49892): (BMAL2 antisense RNA 1)

BMAL2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16573814).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMAL2	NM_020183.6	MANE Select	c.1675A>G	p.Lys559Glu	missense	Exon 16 of 17	NP_064568.3
BMAL2	NM_001394524.1		c.1708A>G	p.Lys570Glu	missense	Exon 16 of 17	NP_001381453.1
BMAL2	NM_001394525.1		c.1666A>G	p.Lys556Glu	missense	Exon 15 of 16	NP_001381454.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMAL2	ENST00000266503.10	TSL:1 MANE Select	c.1675A>G	p.Lys559Glu	missense	Exon 16 of 17	ENSP00000266503.5	Q8WYA1-1
BMAL2	ENST00000311001.9	TSL:1	c.1633A>G	p.Lys545Glu	missense	Exon 15 of 16	ENSP00000312247.5	Q8WYA1-2
BMAL2	ENST00000395901.6	TSL:1	c.1564A>G	p.Lys522Glu	missense	Exon 14 of 15	ENSP00000379238.2	Q8WYA1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.00095

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.62

M_CAP

Benign

0.0028

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

PhyloP100

0.99

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.66

REVEL

Benign

0.10

Sift

Benign

0.25

Sift4G

Benign

0.93

Polyphen

0.44

Vest4

0.22

MutPred

0.32

Gain of catalytic residue at P563 (P = 0)

MVP

0.37

MPC

0.16

ClinPred

0.46

GERP RS

-0.69

Varity_R

0.048

gMVP

0.25

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over