rs368270996
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP6_Moderate
The NM_001164507.2(NEB):āc.5174T>Cā(p.Phe1725Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ).
Frequency
Genomes: š 0.000040 ( 0 hom., cov: 32)
Exomes š: 0.0000068 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
4
8
6
Clinical Significance
Conservation
PhyloP100: 2.85
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;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.765
BP6
?
Variant 2-151665397-A-G is Benign according to our data. Variant chr2-151665397-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 577311.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.5174T>C | p.Phe1725Ser | missense_variant | 42/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.5174T>C | p.Phe1725Ser | missense_variant | 42/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.5174T>C | p.Phe1725Ser | missense_variant | 42/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.5174T>C | p.Phe1725Ser | missense_variant | 42/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.5174T>C | p.Phe1725Ser | missense_variant | 42/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000396 AC: 6AN: 151530Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249132Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135144
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461594Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727082
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GnomAD4 genome ? AF: 0.0000396 AC: 6AN: 151530Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 73956
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;M;M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;.;.
REVEL
Benign
Sift
Uncertain
D;T;.;T;D;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
0.97
.;.;.;.;D;.;.
Vest4
MVP
MPC
0.33
ClinPred
D
GERP RS
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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