chr12-26122509-G-A

Position:

chr12-26122509-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_030762.3(BHLHE41):c.1006C>T(p.Pro336Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,302,852 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

BHLHE41
NM_030762.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

Variant links:

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]

BHLHE41 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3221102).

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3 linkuse as main transcript	c.1006C>T	p.Pro336Ser	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4 linkuse as main transcript	c.-31+357G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BHLHE41	ENST00000242728.5 linkuse as main transcript	c.1006C>T	p.Pro336Ser	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5 linkuse as main transcript	c.-31+357G>A		intron_variant		4
SSPN	ENST00000534829.5 linkuse as main transcript	n.101+357G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

147052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000672

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000211

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

52866

Hom.:

AF XY:

0.0000990

AC XY:

AN XY:

30294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000892

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:

0.000110

Gnomad OTH exome

AF:

0.000634

GnomAD4 exome

AF:

0.000176

AC:

203

AN:

1155800

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

564690

show subpopulations

Gnomad4 AFR exome

AF:

0.0000850

Gnomad4 AMR exome

AF:

0.0000512

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000381

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000246

GnomAD4 genome

AF:

0.000116

AC:

AN:

147052

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

71616

show subpopulations

Gnomad4 AFR

AF:

0.0000246

Gnomad4 AMR

AF:

0.0000672

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000111

Gnomad4 NFE

AF:

0.000211

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.1006C>T (p.P336S) alteration is located in exon 5 (coding exon 5) of the BHLHE41 gene. This alteration results from a C to T substitution at nucleotide position 1006, causing the proline (P) at amino acid position 336 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.62

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.32

REVEL

Benign

0.21

Sift

Benign

0.41

Sift4G

Benign

0.42

Polyphen

0.98

Vest4

0.18

MutPred

0.36

Gain of catalytic residue at G334 (P = 0);

MVP

0.22

ClinPred

0.10

GERP RS

2.1

Varity_R

0.062

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over