Variant 12-26122364-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_030762.3(BHLHE41):c.1151C>T(p.Pro384Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 1,180,500 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P384Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.21

Variant links:

Genes affected

BHLHE41 (HGNC:16617): (basic helix-loop-helix family member e41) This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. Defects in this gene are associated with the short sleep phenotype. [provided by RefSeq, Feb 2014]

BHLHE41 links:

SSPN (HGNC:11322): (sarcospan) This gene encodes a member of the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Two alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

SSPN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-26122364-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BHLHE41	NM_030762.3 linkuse as main transcript	c.1151C>T	p.Pro384Leu	missense_variant	5/5	ENST00000242728.5	NP_110389.1
SSPN	XM_011520853.4 linkuse as main transcript	c.-31+212G>A		intron_variant			XP_011519155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
BHLHE41	ENST00000242728.5 linkuse as main transcript	c.1151C>T	p.Pro384Leu	missense_variant	5/5	1	NM_030762.3	ENSP00000242728	P1
SSPN	ENST00000538142.5 linkuse as main transcript	c.-31+212G>A		intron_variant		4		ENSP00000445360
SSPN	ENST00000534829.5 linkuse as main transcript	n.101+212G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000203

AC:

AN:

147602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000453

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000194

AC:

AN:

1032898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

490622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000203

AC:

AN:

147602

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

71886

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000453

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

0.096

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.013

Polyphen

0.84

Vest4

0.33

MutPred

0.59

Gain of catalytic residue at Y389 (P = 5e-04);

MVP

0.64

ClinPred

0.83

GERP RS

3.1

Varity_R

0.12

gMVP

0.69

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over