rs144836165
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1
The NM_001164508.2(NEB):c.11911-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,593,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
NEB
NM_001164508.2 splice_polypyrimidine_tract, intron
NM_001164508.2 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.828
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 -14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 2-151610640-A-G is Benign according to our data. Variant chr2-151610640-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000499 (76/152388) while in subpopulation EAS AF= 0.0142 (74/5196). AF 95% confidence interval is 0.0116. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.11911-17T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000427231.7 | NP_001157979.2 | |||
NEB | NM_001164508.2 | c.11911-17T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.11911-17T>C | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_001164508.2 | ENSP00000380505 | P5 | |||
NEB | ENST00000427231.7 | c.11911-17T>C | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_001164507.2 | ENSP00000416578 | A2 | |||
NEB | ENST00000409198.5 | c.11182-17T>C | splice_polypyrimidine_tract_variant, intron_variant | 5 | ENSP00000386259 |
Frequencies
GnomAD3 genomes AF: 0.000493 AC: 75AN: 152270Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00113 AC: 282AN: 248926Hom.: 0 AF XY: 0.000940 AC XY: 127AN XY: 135046
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GnomAD4 exome AF: 0.000314 AC: 453AN: 1441284Hom.: 0 Cov.: 28 AF XY: 0.000302 AC XY: 217AN XY: 718258
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GnomAD4 genome AF: 0.000499 AC: 76AN: 152388Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40AN XY: 74522
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Nemaline myopathy 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
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