12-26122193-A-G

Position:

• chr12-26122193-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030762.3(BHLHE41):​c.1322T>C​(p.Leu441Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,444,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.68

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]

SSPN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015196443).
• BP6: Variant 12-26122193-A-G is Benign according to our data. Variant chr12-26122193-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2347182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BHLHE41	NM_030762.3	c.1322T>C	p.Leu441Pro	missense_variant	5/5	ENST00000242728.5	NP_110389.1
SSPN	XM_011520853.4	c.-31+41A>G		intron_variant			XP_011519155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BHLHE41	ENST00000242728.5	c.1322T>C	p.Leu441Pro	missense_variant	5/5	1	NM_030762.3	ENSP00000242728.4
SSPN	ENST00000538142.5	c.-31+41A>G		intron_variant		4		ENSP00000445360.1
SSPN	ENST00000534829.5	n.101+41A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 87 AN: 150512 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000968

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000967

GnomAD3 exomes AF: 0.000368 AC: 25 AN: 67910 Hom.: 0 AF XY: 0.000312 AC XY: 12 AN XY: 38430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000606

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000873 AC: 1129 AN: 1293744 Hom.: 1 Cov.: 30 AF XY: 0.000858 AC XY: 545 AN XY: 635550

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.000522

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000228

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.000587

GnomAD4 genome AF: 0.000578 AC: 87 AN: 150512 Hom.: 0 Cov.: 31 AF XY: 0.000463 AC XY: 34 AN XY: 73460

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.000527

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000968

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000967

Alfa AF: 0.000370 Hom.: 0

Bravo AF: 0.000563

ExAC AF: 0.0000369 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.46
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.27	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.1	N
REVEL	Benign	0.16
Sift	Benign	0.96	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.20
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.046
gMVP		0.35

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: rs762099021; hg19: chr12-26275126;