12-27390208-G-C

Position:

chr12-27390208-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0700

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
BMAL2	NM_020183.6 link	c.888G>C	p.Glu296Asp	missense_variant	9/17	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.888G>C	p.Glu296Asp	missense_variant	9/17	1	NM_020183.6	ENSP00000266503.5		Q8WYA1-1
BMAL2	ENST00000457040.6 link	c.741G>C	p.Glu247Asp	missense_variant	7/15	1		ENSP00000400185.2		H0Y5R1

Frequencies

GnomAD3 genomes

AF:

0.00785

AC:

1195

AN:

152138

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00147

AC XY:

199

AN XY:

135756

show subpopulations

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.:

Cov.:

AF XY:

0.000682

AC XY:

496

AN XY:

727144

show subpopulations

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.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74454

show subpopulations

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.:

Bravo

AF:

0.00952

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00265

AC:

322

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.54

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

MutationAssessor

Benign

1.9

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

PrimateAI

Benign

0.47

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over