chr2-151654090-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001164507.2(NEB):āc.6817A>Gā(p.Lys2273Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,599,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00030 ( 0 hom., cov: 32)
Exomes š: 0.00033 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 5.74
Genes affected
NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-151654090-T-C is Benign according to our data. Variant chr2-151654090-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331495.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.6817A>G | p.Lys2273Glu | missense_variant | 52/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.6817A>G | p.Lys2273Glu | missense_variant | 52/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.6817A>G | p.Lys2273Glu | missense_variant | 52/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.6817A>G | p.Lys2273Glu | missense_variant | 52/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.6817A>G | p.Lys2273Glu | missense_variant | 52/150 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000360 AC: 86AN: 238940Hom.: 0 AF XY: 0.000316 AC XY: 41AN XY: 129702
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GnomAD4 exome AF: 0.000326 AC: 472AN: 1446908Hom.: 0 Cov.: 27 AF XY: 0.000353 AC XY: 254AN XY: 719676
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GnomAD4 genome AF: 0.000296 AC: 45AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:1Benign:2
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NEB p.Lys2273Glu variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs199700878) and ClinVar (classified as likely benign by Invitae and uncertain significance by Illumina). The variant was identified in control databases in 103 of 270336 chromosomes (1 homozygous) at a frequency of 0.000381 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 20 of 24710 chromosomes (freq: 0.000809), Other in 5 of 6800 chromosomes (freq: 0.000735), European (non-Finnish) in 74 of 125282 chromosomes (freq: 0.000591) and Latino in 4 of 32652 chromosomes (freq: 0.000123), but was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys2273 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2021 | The c.6817A>G (p.K2273E) alteration is located in exon 52 (coding exon 50) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 6817, causing the lysine (K) at amino acid position 2273 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
NEB-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 25, 2023 | The NEB c.6817A>G variant is predicted to result in the amino acid substitution p.Lys2273Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.081% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152510604-T-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;M;M;M;M
MutationTaster
Benign
D;D;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;N;N;.;.
REVEL
Uncertain
Sift
Benign
T;D;.;D;T;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
0.45
.;.;.;.;B;.;.
Vest4
MVP
MPC
0.29
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