rs141088433
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001164507.2(NEB):c.10347+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,470 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0088 ( 10 hom., cov: 32)
Exomes 𝑓: 0.0026 ( 67 hom. )
Consequence
NEB
NM_001164507.2 splice_donor_region, intron
NM_001164507.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00001449
2
Clinical Significance
Conservation
PhyloP100: -0.763
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
Variant 2-151626996-G-A is Benign according to our data. Variant chr2-151626996-G-A is described in ClinVar as [Benign]. Clinvar id is 257718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151626996-G-A is described in Lovd as [Benign]. Variant chr2-151626996-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0088 (1340/152244) while in subpopulation EAS AF= 0.0521 (270/5186). AF 95% confidence interval is 0.047. There are 10 homozygotes in gnomad4. There are 673 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 10 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.10347+6C>T | splice_donor_region_variant, intron_variant | ENST00000427231.7 | |||
NEB | NM_001164508.2 | c.10347+6C>T | splice_donor_region_variant, intron_variant | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.10347+6C>T | splice_donor_region_variant, intron_variant | 5 | NM_001164508.2 | P5 | |||
NEB | ENST00000427231.7 | c.10347+6C>T | splice_donor_region_variant, intron_variant | 5 | NM_001164507.2 | A2 | |||
NEB | ENST00000409198.5 | c.9618+6C>T | splice_donor_region_variant, intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00879 AC: 1337AN: 152126Hom.: 10 Cov.: 32
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GnomAD3 exomes AF: 0.00770 AC: 1915AN: 248838Hom.: 35 AF XY: 0.00682 AC XY: 921AN XY: 134968
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GnomAD4 exome AF: 0.00255 AC: 3733AN: 1461226Hom.: 67 Cov.: 31 AF XY: 0.00244 AC XY: 1777AN XY: 726878
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GnomAD4 genome ? AF: 0.00880 AC: 1340AN: 152244Hom.: 10 Cov.: 32 AF XY: 0.00904 AC XY: 673AN XY: 74442
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2016 | 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. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2017 | Variant summary: The NEB c.10347+6C>T variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 925/120680 control chromosomes (19 homozygotes) at a frequency of 0.0076649, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), suggesting this variant is likely a benign polymorphism. The variant is more common in East Asian sub-population with allele frequency of 5.4% (464/8590 chromosomes). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Therefore, the variant of interest has been classified as Benign. - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 27, 2019 | - - |
Nemaline myopathy 2 Benign:2
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at