rs41277374
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_006393.3(NEBL):c.180G>C(p.Lys60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,607,010 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0038 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0057 ( 32 hom. )
Consequence
NEBL
NM_006393.3 missense
NM_006393.3 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 0.102
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008779794).
BP6
?
Variant 10-20889923-C-G is Benign according to our data. Variant chr10-20889923-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45486.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}. Variant chr10-20889923-C-G is described in Lovd as [Likely_benign].
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEBL | NM_006393.3 | c.180G>C | p.Lys60Asn | missense_variant | 3/28 | ENST00000377122.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEBL | ENST00000377122.9 | c.180G>C | p.Lys60Asn | missense_variant | 3/28 | 1 | NM_006393.3 |
Frequencies
GnomAD3 genomes ? AF: 0.00379 AC: 576AN: 152138Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00413 AC: 1030AN: 249578Hom.: 2 AF XY: 0.00429 AC XY: 578AN XY: 134754
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GnomAD4 exome AF: 0.00567 AC: 8250AN: 1454754Hom.: 32 Cov.: 28 AF XY: 0.00562 AC XY: 4067AN XY: 723810
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GnomAD4 genome ? AF: 0.00378 AC: 576AN: 152256Hom.: 3 Cov.: 32 AF XY: 0.00349 AC XY: 260AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | NEBL: BS1, BS2 - |
Likely benign, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 01, 2016 | Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2020 | This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 20, 2015 | p.Lys60Asn in exon 3 of NEBL: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (423/66580) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs41277374). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2013 | The p.K60N variant (also known as c.180G>C) is located in coding exon 3 of theNEBLgene. This alteration results from a G to C substitution at nucleotide position 180. The lysine at codon 60 is replaced by asparagine, an amino acid with some similar properties. ​​In an initial publication associating NEBLwith dilated cardiomyopathy (DCM), this alteration was identified in a cohort of 260 individuals with DCM and absent in 600 control alleles. This alteration was found to be de novoin a proband with adult onset DCM. Authors subsequently developed a transgenic mouse model, and founder mice with this alteration developed severe heart failure at one year old. Embryos with this alteration did not survive, presenting the possibility of embryonic lethality with the p.K60N alteration(Purevjav E etal. J Am Coll Cardiol. 2010;56(18):1493-1502).However, a later publication denotes that the presence and frequency of this alteration in a large population based database from the Exome Sequencing Project (ESP) creates uncertainty regarding its pathogenicity (Andreasen C etal. Eur J Hum Genet. 2013;21(9):918-928). This variant was previously reported in dbSNP asrs41277374. Based on data from the NHLBI Exome Sequencing Project (ESP), the C-allele has an overall frequency of approximately0.52% (67/12998), having been observed in 0.71% (61/8594) of European American alleles, and in 0.14% (6/4404)of African American alleles studied. Based on data from the 1000 Genomes Project, the C-allele has an overall frequency of approximately0.18% (4/2184). The highest observed frequency was 1.12% (2/178) of Britishchromosomes studied. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence for this variant is conflicting and limited at this time, its clinical significance remains unclear. - |
NEBL-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 27, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Primary dilated cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MutPred
Loss of methylation at K60 (P = 0.0203);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at