12-26122233-C-T

Variant names:

• chr12-26122233-C-T
• rs76117681
• NM_030762.3:c.1282G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_030762.3(BHLHE41):​c.1282G>A​(p.Ala428Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,285,214 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.039 (383 hom., cov: 30)
  • Exomes 𝑓: 0.0037 (267 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.157

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011948943).
• BP6: Variant 12-26122233-C-T is Benign according to our data. Variant chr12-26122233-C-T is described in ClinVar as [Benign]. Clinvar id is 3039300.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE41	NM_030762.3	c.1282G>A	p.Ala428Thr	missense_variant	Exon 5 of 5	ENST00000242728.5	NP_110389.1
SSPN	XM_011520853.4	c.-31+81C>T		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.1282G>A	p.Ala428Thr	missense_variant	Exon 5 of 5	1	NM_030762.3	ENSP00000242728.4
SSPN	ENST00000538142.5	c.-31+81C>T		intron_variant	Intron 1 of 2	4		ENSP00000445360.1
SSPN	ENST00000534829.5	n.101+81C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0395 AC: 5914 AN: 149882 Hom.: 384 Cov.: 30

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00434

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000634

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.00107 AC: 9 AN: 8438 Hom.: 0 AF XY: 0.00113 AC XY: 5 AN XY: 4428

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.0469

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000162

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00366 AC: 4154 AN: 1135216 Hom.: 267 Cov.: 30 AF XY: 0.00330 AC XY: 1798 AN XY: 544788

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.00522

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000161

Gnomad4 FIN exome AF: 0.0000904

Gnomad4 NFE exome AF: 0.000222

Gnomad4 OTH exome AF: 0.00990

GnomAD4 genome AF: 0.0395 AC: 5923 AN: 149998 Hom.: 383 Cov.: 30 AF XY: 0.0381 AC XY: 2788 AN XY: 73246

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.00434

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000634

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000593

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0211 Hom.: 30

Bravo AF: 0.0458

ExAC AF: 0.00209 AC: 34

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BHLHE41-related disorder Benign:1

Feb 18, 2020

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
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.15
Sift	Benign	0.049	D
Sift4G	Uncertain	0.029	D
Polyphen		0.92	P
Vest4		0.076
MVP		0.22
ClinPred		0.028	T
GERP RS		1.9
Varity_R		0.059
gMVP		0.40

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: rs76117681; hg19: chr12-26275166;