chr2-151494232-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):ā€‹c.24508G>Cā€‹(p.Gly8170Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8170E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.65
Variant links:
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]
RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEBNM_001164507.2 linkuse as main transcriptc.24508G>C p.Gly8170Arg missense_variant 174/182 ENST00000427231.7
NEBNM_001164508.2 linkuse as main transcriptc.24508G>C p.Gly8170Arg missense_variant 174/182 ENST00000397345.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.24508G>C p.Gly8170Arg missense_variant 174/1825 NM_001164508.2 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.24508G>C p.Gly8170Arg missense_variant 174/1825 NM_001164507.2 A2P20929-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.90e-7
AC:
1
AN:
1449830
Hom.:
0
Cov.:
31
AF XY:
0.00000139
AC XY:
1
AN XY:
719876
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 04, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1349447). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 8205 of the NEB protein (p.Gly8205Arg). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.027
.;.;T;.;T;T;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.59
T;T;T;T;T;T;.;.
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.63
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Pathogenic
3.5
M;.;.;.;M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.4
N;N;.;N;N;D;.;.
REVEL
Benign
0.26
Sift
Benign
0.063
T;T;.;T;T;T;.;.
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D
Polyphen
0.63
.;.;.;.;P;.;.;.
Vest4
0.69
MutPred
0.40
Gain of MoRF binding (P = 0.0075);.;.;.;Gain of MoRF binding (P = 0.0075);.;.;.;
MVP
0.52
MPC
0.24
ClinPred
0.95
D
GERP RS
6.0
Varity_R
0.13
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-152350746; API