12-27390208-G-C

Position:

• chr12-27390208-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020183.6(BMAL2):​c.888G>C​(p.Glu296Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,892 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (31 hom.)
• Consequence: BMAL2 NM_020183.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0700

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043046772).
• BP6: Variant 12-27390208-G-C is Benign according to our data. Variant chr12-27390208-G-C is described in ClinVar as [Benign]. Clinvar id is 789045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00786 (1196/152256) while in subpopulation AFR AF= 0.0271 (1126/41540). AF 95% confidence interval is 0.0258. There are 16 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMAL2	NM_020183.6	c.888G>C	p.Glu296Asp	missense_variant	9/17	ENST00000266503.10
BMAL2-AS1	NR_109975.1	n.434-40C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMAL2	ENST00000266503.10	c.888G>C	p.Glu296Asp	missense_variant	9/17	1	NM_020183.6	P2
BMAL2-AS1	ENST00000500498.2	n.425-40C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1195 AN: 152138 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00218 AC: 548 AN: 251226 Hom.: 6 AF XY: 0.00147 AC XY: 199 AN XY: 135756

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000813 AC: 1189 AN: 1461636 Hom.: 31 Cov.: 30 AF XY: 0.000682 AC XY: 496 AN XY: 727144

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00786 AC: 1196 AN: 152256 Hom.: 16 Cov.: 32 AF XY: 0.00728 AC XY: 542 AN XY: 74454

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00952

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00265 AC: 322

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	.;.;.;.;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	.;.;.;.;.;L;.
MutationTaster	Benign	0.91	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.092	T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T
Polyphen		0.96	D;P;.;B;P;B;.
Vest4		0.22
MutPred		0.40		.;.;.;.;.;Gain of catalytic residue at E296 (P = 0);.;
MVP		0.27
MPC		0.51
ClinPred		0.063	T
GERP RS		-2.6
Varity_R		0.13
gMVP		0.37

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: rs74988383; hg19: chr12-27543141;