chr10-20889923-C-G
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
Consequence
NM_006393.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00379 AC: 576AN: 152138Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00413 AC: 1030AN: 249578Hom.: 2 AF XY: 0.00429 AC XY: 578AN XY: 134754
GnomAD4 exome AF: 0.00567 AC: 8250AN: 1454754Hom.: 32 Cov.: 28 AF XY: 0.00562 AC XY: 4067AN XY: 723810
GnomAD4 genome AF: 0.00378 AC: 576AN: 152256Hom.: 3 Cov.: 32 AF XY: 0.00349 AC XY: 260AN XY: 74444
ClinVar
Submissions by phenotype
not provided Benign:3
Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes). -
NEBL: BS1, BS2 -
This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259) -
not specified Benign:2
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). -
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Cardiovascular phenotype Uncertain:1
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at