12-26122399-C-G

Variant names:

• chr12-26122399-C-G
• rs140063083
• NM_030762.3:c.1116G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_030762.3(BHLHE41):​c.1116G>C​(p.Leu372Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,283,514 control chromosomes in the GnomAD database, including 772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 30)
  • Exomes 𝑓: 0.033 (713 hom.)
• Consequence: BHLHE41 NM_030762.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.70

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-26122399-C-G is Benign according to our data. Variant chr12-26122399-C-G is described in ClinVar as [Benign]. Clinvar id is 3055569.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0226 (3357/148408) while in subpopulation AMR AF= 0.0377 (567/15026). AF 95% confidence interval is 0.0352. There are 59 homozygotes in gnomad4. There are 1546 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE41	NM_030762.3	c.1116G>C	p.Leu372Leu	synonymous_variant	Exon 5 of 5	ENST00000242728.5	NP_110389.1
SSPN	XM_011520853.4	c.-31+247C>G		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.1116G>C	p.Leu372Leu	synonymous_variant	Exon 5 of 5	1	NM_030762.3	ENSP00000242728.4
SSPN	ENST00000538142.5	c.-31+247C>G		intron_variant	Intron 1 of 2	4		ENSP00000445360.1
SSPN	ENST00000534829.5	n.101+247C>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3359 AN: 148300 Hom.: 59 Cov.: 30

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.00770

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0424

GnomAD3 exomes AF: 0.0232 AC: 1514 AN: 65158 Hom.: 28 AF XY: 0.0215 AC XY: 820 AN XY: 38152

Gnomad AFR exome AF: 0.00414

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.000482

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.00675

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0246

GnomAD4 exome AF: 0.0326 AC: 37036 AN: 1135106 Hom.: 713 Cov.: 30 AF XY: 0.0324 AC XY: 17889 AN XY: 551768

Gnomad4 AFR exome AF: 0.00546

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00653

Gnomad4 FIN exome AF: 0.00734

Gnomad4 NFE exome AF: 0.0362

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0226 AC: 3357 AN: 148408 Hom.: 59 Cov.: 30 AF XY: 0.0214 AC XY: 1546 AN XY: 72354

Gnomad4 AFR AF: 0.00550

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00480

Gnomad4 FIN AF: 0.00770

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0419

Alfa AF: 0.0220 Hom.: 3

Bravo AF: 0.0245

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BHLHE41-related disorder Benign:1

Dec 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.7
DANN	Benign	0.60

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

Other links and lift over

dbSNP: rs140063083; hg19: chr12-26275332;