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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_030762.3(BHLHE41):c.1151C>G(p.Pro384Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,180,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). 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 0.000027 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Affects no assertion criteria provided O:1

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 Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

BS2

High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3 linkuse as main transcript	c.1151C>G	p.Pro384Arg	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4 linkuse as main transcript	c.-31+212G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BHLHE41	ENST00000242728.5 linkuse as main transcript	c.1151C>G	p.Pro384Arg	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5 linkuse as main transcript	c.-31+212G>C		intron_variant		4
SSPN	ENST00000534829.5 linkuse as main transcript	n.101+212G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000271

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:

0.0000604

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000387

AC:

AN:

1032896

Hom.:

Cov.:

AF XY:

0.0000326

AC XY:

AN XY:

490620

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:

0.0000477

Gnomad4 FIN exome

AF:

0.0000967

Gnomad4 NFE exome

AF:

0.0000383

Gnomad4 OTH exome

AF:

0.0000763

GnomAD4 genome

AF:

0.0000271

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:

0.0000604

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000513

Hom.:

ExAC

AF:

0.0000422

AC:

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Short sleep, familial natural, 1

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Aug 14, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.35

MutationAssessor

Benign

0.81

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.60

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.76

MutPred

0.73

Gain of catalytic residue at Y389 (P = 0);

MVP

0.69

ClinPred

0.88

GERP RS

3.1

Varity_R

0.23

gMVP

0.65

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