rs370572955

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001164507.2(NEB):​c.9853C>T​(p.Arg3285Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,613,540 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

7
6
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.9853C>T p.Arg3285Cys missense_variant 69/182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.9853C>T p.Arg3285Cys missense_variant 69/182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.9853C>T p.Arg3285Cys missense_variant 69/1825 NM_001164508.2 ENSP00000380505 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.9853C>T p.Arg3285Cys missense_variant 69/1825 NM_001164507.2 ENSP00000416578 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.9124C>T p.Arg3042Cys missense_variant 66/1505 ENSP00000386259 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151978
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000402
AC:
10
AN:
248990
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135064
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000787
AC:
115
AN:
1461562
Hom.:
1
Cov.:
32
AF XY:
0.0000646
AC XY:
47
AN XY:
727040
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000801
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151978
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74196
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000244
AC:
2
ExAC
AF:
0.0000414
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 19, 2022This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3285 of the NEB protein (p.Arg3285Cys). This variant is present in population databases (rs370572955, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465657). 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"). In 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. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 06, 2023- -
Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 25, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.22
.;.;T;.;D;.;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;.;.
M_CAP
Benign
0.060
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
3.3
M;.;.;.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-3.6
D;D;.;D;D;.;.
REVEL
Uncertain
0.42
Sift
Benign
0.066
T;D;.;D;T;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.
Vest4
0.65
MVP
0.72
MPC
0.087
ClinPred
0.91
D
GERP RS
5.6
Varity_R
0.33
gMVP
0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370572955; hg19: chr2-152484327; API