Genetic Variant NM_030762.3:c.1337C>G (chr12-26122178-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_030762.3(BHLHE41):c.1337C>G(p.Pro446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,498,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24502778).

BS2

High AC in GnomAdExome4 at 23 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.1337C>G	p.Pro446Arg	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.1337C>G	p.Pro446Arg	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
BHLHE41	ENST00000957109.1		c.1343C>G	p.Pro448Arg	missense	Exon 5 of 5	ENSP00000627168.1
SSPN	ENST00000538142.5	TSL:4	c.-31+26G>C		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151586

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000101

AC:

AN:

98596

AF XY:

0.00

show subpopulations

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:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1347188

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

663322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28110

American (AMR)

AF:

0.0000352

AC:

AN:

28420

Ashkenazi Jewish (ASJ)

AF:

0.0000426

AC:

AN:

23448

East Asian (EAS)

AF:

0.00

AC:

AN:

32320

South Asian (SAS)

AF:

0.00

AC:

AN:

72266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4670

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1056210

Other (OTH)

AF:

0.00

AC:

AN:

55512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000132

AC:

AN:

151586

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41340

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67844

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.90

PhyloP100

1.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.84

REVEL

Benign

0.25

Sift

Uncertain

0.011

Sift4G

Benign

0.17

Polyphen

0.98

Vest4

0.17

MVP

0.40

ClinPred

0.19

GERP RS

2.8

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.10

gMVP

0.32

Mutation Taster

=81/19

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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