Variant chr12-27385531-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020183.6(BMAL2):c.535G>C(p.Asp179His) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BMAL2
NM_020183.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34708887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMAL2	NM_020183.6 link	c.535G>C	p.Asp179His	missense_variant	6/17	ENST00000266503.10	NP_064568.3	Q8WYA1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMAL2	ENST00000266503.10 link	c.535G>C	p.Asp179His	missense_variant	6/17	1	NM_020183.6	ENSP00000266503.5		Q8WYA1-1
BMAL2	ENST00000457040.6 link	c.388G>C	p.Asp130His	missense_variant	4/15	1		ENSP00000400185.2		H0Y5R1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453374

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723574

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2024

The c.535G>C (p.D179H) alteration is located in exon 6 (coding exon 6) of the ARNTL2 gene. This alteration results from a G to C substitution at nucleotide position 535, causing the aspartic acid (D) at amino acid position 179 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;.;.;.;.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D

M_CAP

Benign

0.0054

MetaRNN

Benign

0.35

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

1.9

.;.;.;.;.;L;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.8

D;D;D;D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.025

D;D;D;D;D;D;D

Sift4G

Uncertain

0.059

T;T;D;T;T;T;T

Polyphen

0.96

D;P;.;P;P;P;.

Vest4

0.53

MutPred

0.54

.;.;.;.;.;Gain of catalytic residue at N180 (P = 0.0022);.;

MVP

0.30

MPC

0.20

ClinPred

0.99

GERP RS

3.7

Varity_R

0.43

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over