Genetic Variant NM_030762.3:c.1151C>G (chr12-26122364-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -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).

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

Publications

15 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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

BS2

High AC in GnomAdExome4 at 40 AD gene.

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.1151C>G	p.Pro384Arg	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.1151C>G	p.Pro384Arg	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
BHLHE41	ENST00000957109.1		c.1157C>G	p.Pro386Arg	missense	Exon 5 of 5	ENSP00000627168.1
SSPN	ENST00000538142.5	TSL:4	c.-31+212G>C		intron	N/A	ENSP00000445360.1	F5H381

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

10992

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:

0.0000387

AC:

AN:

1032896

Hom.:

Cov.:

AF XY:

0.0000326

AC XY:

AN XY:

490620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20728

American (AMR)

AF:

0.00

AC:

AN:

7456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11842

East Asian (EAS)

AF:

0.00

AC:

AN:

21140

South Asian (SAS)

AF:

0.0000477

AC:

AN:

20982

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

20688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2758

European-Non Finnish (NFE)

AF:

0.0000383

AC:

AN:

888006

Other (OTH)

AF:

0.0000763

AC:

AN:

39296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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

AF:

0.0000271

AC:

AN:

147602

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

71886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40782

American (AMR)

AF:

0.00

AC:

AN:

14928

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00

AC:

AN:

4928

South Asian (SAS)

AF:

0.00

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000604

AC:

AN:

66276

Other (OTH)

AF:

0.00

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000295

Hom.:

ExAC

AF:

0.0000422

AC:

ClinVar

ClinVar submissions

Significance:Affects

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Short sleep, familial natural, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

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

PhyloP100

8.2

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

PromoterAI

-0.00060

Neutral

(source)

Varity_R

0.23

gMVP

0.65

Mutation Taster

=60/40

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over