chr12-26122375-C-T

Variant names:

• chr12-26122375-C-T
• rs998139698
• NM_030762.3:c.1140G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_030762.3(BHLHE41):​c.1140G>A​(p.Ala380Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BHLHE41 NM_030762.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.795
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-26122375-C-T is Benign according to our data. Variant chr12-26122375-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3351167.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.795 with no splicing effect.

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.1140G>A	p.Ala380Ala	synonymous	Exon 5 of 5	NP_110389.1	Q9C0J9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE41	ENST00000242728.5	TSL:1 MANE Select	c.1140G>A	p.Ala380Ala	synonymous	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
	BHLHE41	ENST00000957109.1		c.1146G>A	p.Ala382Ala	synonymous	Exon 5 of 5	ENSP00000627168.1
	SSPN	ENST00000538142.5	TSL:4	c.-31+223C>T		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.47e-7 AC: 1 AN: 1056454 Hom.: 0 Cov.: 30 AF XY: 0.00000199 AC XY: 1 AN XY: 503480

African (AFR) AF: 0.00 AC: 0 AN: 21422

American (AMR) AF: 0.00 AC: 0 AN: 8922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13054

East Asian (EAS) AF: 0.00 AC: 0 AN: 22608

South Asian (SAS) AF: 0.00 AC: 0 AN: 22978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2982

European-Non Finnish (NFE) AF: 0.00000111 AC: 1 AN: 901280

Other (OTH) AF: 0.00 AC: 0 AN: 40658

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BHLHE41-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.8
DANN	Benign	0.90
PhyloP100		0.80
PromoterAI		-0.045	Neutral

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

Other links and lift over

dbSNP: rs998139698; hg19: chr12-26275308;