12-26122347-G-A

Variant names:

• chr12-26122347-G-A
• rs752651978
• NM_030762.3:c.1168C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_030762.3(BHLHE41):​c.1168C>T​(p.Pro390Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,182,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42
• 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 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.1168C>T	p.Pro390Ser	missense	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.1168C>T	p.Pro390Ser	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
	BHLHE41	ENST00000957109.1		c.1174C>T	p.Pro392Ser	missense	Exon 5 of 5	ENSP00000627168.1
	SSPN	ENST00000538142.5	TSL:4	c.-31+195G>A		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes AF: 0.0000338 AC: 5 AN: 147936 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 2468 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000165 AC: 171 AN: 1034432 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 86 AN XY: 490130

African (AFR) AF: 0.00 AC: 0 AN: 20882

American (AMR) AF: 0.00 AC: 0 AN: 6782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11734

East Asian (EAS) AF: 0.00 AC: 0 AN: 21776

South Asian (SAS) AF: 0.00 AC: 0 AN: 19548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20658

Middle Eastern (MID) AF: 0.000371 AC: 1 AN: 2692

European-Non Finnish (NFE) AF: 0.000181 AC: 161 AN: 890622

Other (OTH) AF: 0.000226 AC: 9 AN: 39738

GnomAD4 genome AF: 0.0000338 AC: 5 AN: 147936 Hom.: 0 Cov.: 30 AF XY: 0.0000278 AC XY: 2 AN XY: 72044

African (AFR) AF: 0.00 AC: 0 AN: 40858

American (AMR) AF: 0.00 AC: 0 AN: 14968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000755 AC: 5 AN: 66266

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.0000247 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.0035
Eigen_PC	Benign	-0.0044
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.026	D
Polyphen		0.37	B
Vest4		0.26
MutPred		0.39		Gain of catalytic residue at Y389 (P = 0)
MVP		0.45
ClinPred		0.97	D
GERP RS		3.1
PromoterAI		0.026	Neutral
Varity_R		0.38
gMVP		0.73
Mutation Taster		=70/30	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: rs752651978; hg19: chr12-26275280;