NM_030762.3:c.1116G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3357 AD gene.

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.1116G>C	p.Leu372Leu	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.1116G>C	p.Leu372Leu	synonymous	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
	BHLHE41	ENST00000957109.1		c.1122G>C	p.Leu374Leu	synonymous	Exon 5 of 5	ENSP00000627168.1
	SSPN	ENST00000538142.5	TSL:4	c.-31+247C>G		intron	N/A	ENSP00000445360.1	F5H381

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

GnomAD2 exomes AF: 0.0232 AC: 1514 AN: 65158 AF XY: 0.0215

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 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

African (AFR) AF: 0.00546 AC: 129 AN: 23606

American (AMR) AF: 0.0266 AC: 488 AN: 18334

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 579 AN: 16654

East Asian (EAS) AF: 0.00 AC: 0 AN: 23904

South Asian (SAS) AF: 0.00653 AC: 251 AN: 38410

European-Finnish (FIN) AF: 0.00734 AC: 194 AN: 26448

Middle Eastern (MID) AF: 0.0246 AC: 89 AN: 3618

European-Non Finnish (NFE) AF: 0.0362 AC: 34085 AN: 940308

Other (OTH) AF: 0.0279 AC: 1221 AN: 43824

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

African (AFR) AF: 0.00550 AC: 226 AN: 41084

American (AMR) AF: 0.0377 AC: 567 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 115 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5014

South Asian (SAS) AF: 0.00480 AC: 23 AN: 4794

European-Finnish (FIN) AF: 0.00770 AC: 72 AN: 9348

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.0335 AC: 2225 AN: 66458

Other (OTH) AF: 0.0419 AC: 87 AN: 2074

Alfa AF: 0.0220 Hom.: 3

Bravo AF: 0.0245

ClinVar

ClinVar submissions

Significance: 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	-0.63
CADD	Benign	8.7
DANN	Benign	0.60
PhyloP100		1.7
PromoterAI		-0.041	Neutral
Mutation Taster		=100/0	polymorphism

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: rs140063083; hg19: chr12-26275332;