rs2290034

Variant names:

• chr11-13385637-C-T
• rs2290034
• NM_001297719.2:c.1618-52C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001297719.2(BMAL1):​c.1618-52C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,362,966 control chromosomes in the GnomAD database, including 23,457 homozygotes. 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: 𝑓 0.19 (2863 hom., cov: 32)
  • Exomes 𝑓: 0.18 (20594 hom.)
• Consequence: BMAL1 NM_001297719.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 8 publications found

Genes affected

BMAL1 (HGNC:701): (basic helix-loop-helix ARNT like 1) The protein encoded by this gene is a basic helix-loop-helix protein that forms a heterodimer with CLOCK. This heterodimer binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, and altered sleep patterns. The protein regulates interferon-stimulated gene expression and is an important factor in viral infection, including COVID-19. [provided by RefSeq, Oct 2021]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297719.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL1	NM_001297719.2	MANE Select	c.1618-52C>T		intron	N/A	NP_001284648.1	O00327-2
	BMAL1	NM_001351807.2		c.1633-52C>T		intron	N/A	NP_001338736.1
	BMAL1	NM_001351814.2		c.1633-52C>T		intron	N/A	NP_001338743.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL1	ENST00000403290.6	TSL:1 MANE Select	c.1618-52C>T		intron	N/A	ENSP00000384517.1	O00327-2
	BMAL1	ENST00000389707.8	TSL:1	c.1615-52C>T		intron	N/A	ENSP00000374357.4	O00327-8
	BMAL1	ENST00000403482.7	TSL:1	c.1612-52C>T		intron	N/A	ENSP00000385897.3	O00327-7

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29168 AN: 152018 Hom.: 2854 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.179 AC: 216950 AN: 1210830 Hom.: 20594 Cov.: 16 AF XY: 0.176 AC XY: 107762 AN XY: 610892

African (AFR) AF: 0.209 AC: 5896 AN: 28228

American (AMR) AF: 0.319 AC: 13260 AN: 41600

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2521 AN: 24068

East Asian (EAS) AF: 0.191 AC: 7259 AN: 38084

South Asian (SAS) AF: 0.127 AC: 10108 AN: 79398

European-Finnish (FIN) AF: 0.213 AC: 11135 AN: 52378

Middle Eastern (MID) AF: 0.0901 AC: 467 AN: 5182

European-Non Finnish (NFE) AF: 0.177 AC: 157380 AN: 890154

Other (OTH) AF: 0.172 AC: 8924 AN: 51738

GnomAD4 genome AF: 0.192 AC: 29212 AN: 152136 Hom.: 2863 Cov.: 32 AF XY: 0.193 AC XY: 14324 AN XY: 74382

African (AFR) AF: 0.212 AC: 8816 AN: 41488

American (AMR) AF: 0.254 AC: 3883 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 359 AN: 3466

East Asian (EAS) AF: 0.169 AC: 873 AN: 5170

South Asian (SAS) AF: 0.127 AC: 612 AN: 4818

European-Finnish (FIN) AF: 0.219 AC: 2315 AN: 10586

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11793 AN: 67998

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.173 Hom.: 1550

Bravo AF: 0.198

Asia WGS AF: 0.145 AC: 503 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.40
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2290034;

hg19: chr11-13407184;