12-27418129-G-C

Position:

• chr12-27418129-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020183.6(BMAL2):​c.1707G>C​(p.Met569Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.570

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03860584).
• BP6: Variant 12-27418129-G-C is Benign according to our data. Variant chr12-27418129-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3134473.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMAL2	NM_020183.6	c.1707G>C	p.Met569Ile	missense_variant	16/17	ENST00000266503.10
BMAL2-AS1	NR_109975.1	n.139-23506C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMAL2	ENST00000266503.10	c.1707G>C	p.Met569Ile	missense_variant	16/17	1	NM_020183.6	P2
BMAL2-AS1	ENST00000500498.2	n.130-23506C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.8
DANN	Benign	0.86
DEOGEN2	Benign	0.0024	.;.;.;.;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.64	T;T;T;T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	.;.;.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.16	N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.48	T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.
Vest4		0.099
MutPred		0.31		.;.;.;.;Gain of catalytic residue at M569 (P = 0.0081);.;
MVP		0.18
MPC		0.12
ClinPred		0.13	T
GERP RS		-0.66
Varity_R		0.034
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-27571062;