chr12-26122222-C-CGCG

Variant names:

• chr12-26122222-C-CGCG
• rs1375835308
• NM_030762.3:c.1290_1292dupCGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_030762.3(BHLHE41):​c.1290_1292dupCGC​(p.Ala431dup) variant causes a disruptive 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: BHLHE41 NM_030762.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_030762.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: 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 no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE41	NM_030762.3	c.1290_1292dupCGC	p.Ala431dup	disruptive_inframe_insertion	Exon 5 of 5	ENST00000242728.5	NP_110389.1
SSPN	XM_011520853.4	c.-31+80_-31+82dupGCG		intron_variant	Intron 1 of 2		XP_011519155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BHLHE41	ENST00000242728.5	c.1290_1292dupCGC	p.Ala431dup	disruptive_inframe_insertion	Exon 5 of 5	1	NM_030762.3	ENSP00000242728.4
SSPN	ENST00000538142.5	c.-31+80_-31+82dupGCG		intron_variant	Intron 1 of 2	4		ENSP00000445360.1
SSPN	ENST00000534829.5	n.101+80_101+82dupGCG		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000518 AC: 78 AN: 150464 Hom.: 0 Cov.: 30

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

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 AF: 0.000518 AC: 78 AN: 150570 Hom.: 0 Cov.: 30 AF XY: 0.000517 AC XY: 38 AN XY: 73512

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: no assertion criteria provided

Submissions by phenotype

BHLHE41-related disorder Benign:1

May 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1375835308; hg19: chr12-26275155;