rs183354017

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164508.2(NEB):ā€‹c.8024A>Gā€‹(p.Asp2675Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,613,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00026 ( 0 hom., cov: 33)
Exomes š‘“: 0.00015 ( 1 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.192
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.050138026).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.8024A>G p.Asp2675Gly missense_variant 58/182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.8024A>G p.Asp2675Gly missense_variant 58/182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.8024A>G p.Asp2675Gly missense_variant 58/1825 NM_001164508.2 ENSP00000380505 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.8024A>G p.Asp2675Gly missense_variant 58/1825 NM_001164507.2 ENSP00000416578 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.8024A>G p.Asp2675Gly missense_variant 58/1505 ENSP00000386259 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000108
AC:
27
AN:
249056
Hom.:
0
AF XY:
0.0000962
AC XY:
13
AN XY:
135104
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.000148
AC:
216
AN:
1461640
Hom.:
1
Cov.:
31
AF XY:
0.000129
AC XY:
94
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000153
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.000255
AC XY:
19
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000417
Hom.:
0
Bravo
AF:
0.000484
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 17, 2019This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 30, 2024The c.8024A>G (p.D2675G) alteration is located in exon 58 (coding exon 56) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 8024, causing the aspartic acid (D) at amino acid position 2675 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 07, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.033
.;.;T;.;T;.;.
Eigen
Benign
-0.097
Eigen_PC
Benign
0.069
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;.;.
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.050
T;T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.6
L;L;.;L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.8
N;N;.;N;N;.;.
REVEL
Benign
0.11
Sift
Benign
0.099
T;T;.;T;T;.;.
Sift4G
Uncertain
0.017
D;T;T;T;D;T;T
Polyphen
0.21
.;.;.;.;B;.;.
Vest4
0.52
MVP
0.45
MPC
0.11
ClinPred
0.11
T
GERP RS
5.7
Varity_R
0.11
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs183354017; hg19: chr2-152499800; API