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12-26122222-C-CGCG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PM4_SupportingBP6_ModerateBS2

The NM_030762.3(BHLHE41):c.1292_1293insCGC(p.Ala430dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000484 in 1,302,010 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

BHLHE41
NM_030762.3 inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.13
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 Likely_benign. Variant got -5 ACMG points.

PM4
?
    PM4 - Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Nonframeshift variant in NON repetitive region in NM_030762.3. Strenght limited to Supporting due to length of the change: 1aa.
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 12-26122222-C-CGCG is Benign according to our data. Variant chr12-26122222-C-CGCG is described in ClinVar as [Likely_benign]. Clinvar id is 3046119.Status of the report is criteria_provided_single_submitter, 1 stars.
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 78 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BHLHE41NM_030762.3 linkuse as main transcriptc.1292_1293insCGC p.Ala430dup inframe_insertion 5/5 ENST00000242728.5
SSPNXM_011520853.4 linkuse as main transcriptc.-31+80_-31+82dup intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BHLHE41ENST00000242728.5 linkuse as main transcriptc.1292_1293insCGC p.Ala430dup inframe_insertion 5/51 NM_030762.3 P1
SSPNENST00000538142.5 linkuse as main transcriptc.-31+80_-31+82dup intron_variant 4
SSPNENST00000534829.5 linkuse as main transcriptn.101+80_101+82dup intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000518
AC:
78
AN:
150464
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000707
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00112
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000982
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000399
Gnomad OTH
AF:
0.00194
GnomAD4 exome
AF:
0.000479
AC:
552
AN:
1151440
Hom.:
0
Cov.:
30
AF XY:
0.000502
AC XY:
278
AN XY:
554154
show subpopulations
Gnomad4 AFR exome
AF:
0.000261
Gnomad4 AMR exome
AF:
0.000578
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000377
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000280
Gnomad4 NFE exome
AF:
0.000549
Gnomad4 OTH exome
AF:
0.000282
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000518
AC:
78
AN:
150570
Hom.:
0
Cov.:
30
AF XY:
0.000517
AC XY:
38
AN XY:
73512
show subpopulations
Gnomad4 AFR
AF:
0.000705
Gnomad4 AMR
AF:
0.00112
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000982
Gnomad4 NFE
AF:
0.000400
Gnomad4 OTH
AF:
0.00192
Alfa
AF:
0.000498
Hom.:
0
Asia WGS
AF:
0.000291
AC:
1
AN:
3452

ClinVar

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

Submissions by phenotype

BHLHE41-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 22, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1375835308; hg19: chr12-26275155; API