rs115631125
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001164508.2(NEB):c.19056G>T(p.Thr6352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,608,264 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0061 ( 63 hom. )
Consequence
NEB
NM_001164508.2 synonymous
NM_001164508.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -5.15
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 2-151561253-C-A is Benign according to our data. Variant chr2-151561253-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 129716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151561253-C-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-5.15 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00395 (601/152260) while in subpopulation SAS AF= 0.0145 (70/4820). AF 95% confidence interval is 0.0118. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.19056G>T | p.Thr6352= | synonymous_variant | 122/182 | ENST00000427231.7 | NP_001157979.2 | |
NEB | NM_001164508.2 | c.19056G>T | p.Thr6352= | synonymous_variant | 122/182 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.19056G>T | p.Thr6352= | synonymous_variant | 122/182 | 5 | NM_001164508.2 | ENSP00000380505 | P5 | |
NEB | ENST00000427231.7 | c.19056G>T | p.Thr6352= | synonymous_variant | 122/182 | 5 | NM_001164507.2 | ENSP00000416578 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00396 AC: 602AN: 152142Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00575 AC: 1381AN: 240254Hom.: 13 AF XY: 0.00656 AC XY: 853AN XY: 130022
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GnomAD4 exome AF: 0.00612 AC: 8913AN: 1456004Hom.: 63 Cov.: 31 AF XY: 0.00650 AC XY: 4705AN XY: 723712
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GnomAD4 genome AF: 0.00395 AC: 601AN: 152260Hom.: 3 Cov.: 32 AF XY: 0.00412 AC XY: 307AN XY: 74442
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 23, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 11, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Nemaline myopathy 2 Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | NEB: BP4, BP7, BS1, BS2 - |
Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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