chr12-26122169-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030762.3(BHLHE41):c.1346C>T(p.Pro449Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,356,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. P449Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10854858).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030762.3. 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
	BHLHE41	NM_030762.3	MANE Select	c.1346C>T	p.Pro449Leu	missense	Exon 5 of 5	NP_110389.1	Q9C0J9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BHLHE41	ENST00000242728.5	TSL:1 MANE Select	c.1346C>T	p.Pro449Leu	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
BHLHE41	ENST00000957109.1		c.1352C>T	p.Pro451Leu	missense	Exon 5 of 5	ENSP00000627168.1
SSPN	ENST00000538142.5	TSL:4	c.-31+17G>A		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

110826

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000295

AC:

AN:

1356924

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

668170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28692

American (AMR)

AF:

0.00

AC:

AN:

30254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23864

East Asian (EAS)

AF:

0.00

AC:

AN:

32754

South Asian (SAS)

AF:

0.00

AC:

AN:

73786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4802

European-Non Finnish (NFE)

AF:

0.00000283

AC:

AN:

1060238

Other (OTH)

AF:

0.0000179

AC:

AN:

55952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.81

PhyloP100

1.1

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

REVEL

Benign

0.19

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.011

Polyphen

0.0

Vest4

0.12

MutPred

0.22

Gain of catalytic residue at G451 (P = 0.0061)

MVP

0.47

ClinPred

0.40

GERP RS

1.7

PromoterAI

-0.20

Neutral

(source)

Varity_R

0.14

gMVP

0.39

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over