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GeneBe

12-26122435-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_030762.3(BHLHE41):c.1080C>G(p.Ala360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000407 in 1,354,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00040 ( 2 hom. )

Consequence

BHLHE41
NM_030762.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.322
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-26122435-G-C is Benign according to our data. Variant chr12-26122435-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 712110.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.322 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 69 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BHLHE41NM_030762.3 linkuse as main transcriptc.1080C>G p.Ala360= synonymous_variant 5/5 ENST00000242728.5
SSPNXM_011520853.4 linkuse as main transcriptc.-31+283G>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BHLHE41ENST00000242728.5 linkuse as main transcriptc.1080C>G p.Ala360= synonymous_variant 5/51 NM_030762.3 P1
SSPNENST00000538142.5 linkuse as main transcriptc.-31+283G>C intron_variant 4
SSPNENST00000534829.5 linkuse as main transcriptn.101+283G>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000464
AC:
69
AN:
148774
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000974
Gnomad AMI
AF:
0.0307
Gnomad AMR
AF:
0.000400
Gnomad ASJ
AF:
0.000293
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000434
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000472
AC:
37
AN:
78338
Hom.:
1
AF XY:
0.000509
AC XY:
23
AN XY:
45204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000456
Gnomad ASJ exome
AF:
0.000170
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000469
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000655
Gnomad OTH exome
AF:
0.000975
GnomAD4 exome
AF:
0.000400
AC:
482
AN:
1205826
Hom.:
2
Cov.:
30
AF XY:
0.000446
AC XY:
264
AN XY:
592478
show subpopulations
Gnomad4 AFR exome
AF:
0.0000405
Gnomad4 AMR exome
AF:
0.000404
Gnomad4 ASJ exome
AF:
0.0000523
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000342
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000423
Gnomad4 OTH exome
AF:
0.000614
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000463
AC:
69
AN:
148882
Hom.:
0
Cov.:
30
AF XY:
0.000468
AC XY:
34
AN XY:
72636
show subpopulations
Gnomad4 AFR
AF:
0.0000972
Gnomad4 AMR
AF:
0.000399
Gnomad4 ASJ
AF:
0.000293
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000434
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000498
Hom.:
0
Bravo
AF:
0.000552

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeMay 08, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.60
Cadd
Benign
9.4
Dann
Benign
0.51

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.

Other links and lift over

dbSNP: rs776094709; hg19: chr12-26275368; API