rs727505285

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006393.3(NEBL):​c.2499G>T​(p.Arg833Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

12
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.136
Variant links:
Genes affected
NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBLNM_006393.3 linkuse as main transcriptc.2499G>T p.Arg833Ser missense_variant 24/28 ENST00000377122.9 NP_006384.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBLENST00000377122.9 linkuse as main transcriptc.2499G>T p.Arg833Ser missense_variant 24/281 NM_006393.3 ENSP00000366326 O76041-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461678
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727160
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 06, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 30, 2023The c.2499G>T (p.R833S) alteration is located in exon 24 (coding exon 24) of the NEBL gene. This alteration results from a G to T substitution at nucleotide position 2499, causing the arginine (R) at amino acid position 833 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 12, 2023This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 833 of the NEBL protein (p.Arg833Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 180011). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Uncertain
0.088
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.074
T;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.029
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.1
D;N
REVEL
Benign
0.25
Sift
Uncertain
0.0040
D;T
Sift4G
Benign
0.081
T;T
Polyphen
0.95
P;.
Vest4
0.81
MutPred
0.50
Loss of helix (P = 0.0068);.;
MVP
0.67
MPC
0.017
ClinPred
0.98
D
GERP RS
3.7
Varity_R
0.45
gMVP
0.38

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.

Other links and lift over

dbSNP: rs727505285; hg19: chr10-21101717; API