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rs149471462

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001164507.2(NEB):c.3007G>C(p.Val1003Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,612,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1003V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.16
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 -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0457187).
BP6
Variant 2-151680765-C-G is Benign according to our data. Variant chr2-151680765-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465596.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEBNM_001164507.2 linkuse as main transcriptc.3007G>C p.Val1003Leu missense_variant 30/182 ENST00000427231.7
NEBNM_001164508.2 linkuse as main transcriptc.3007G>C p.Val1003Leu missense_variant 30/182 ENST00000397345.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.3007G>C p.Val1003Leu missense_variant 30/1825 NM_001164508.2 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.3007G>C p.Val1003Leu missense_variant 30/1825 NM_001164507.2 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.3007G>C p.Val1003Leu missense_variant 30/1505 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000893
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000763
AC:
19
AN:
249172
Hom.:
0
AF XY:
0.0000444
AC XY:
6
AN XY:
135172
show subpopulations
Gnomad AFR exome
AF:
0.00116
Gnomad AMR exome
AF:
0.0000290
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1460576
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
726662
show subpopulations
Gnomad4 AFR exome
AF:
0.00129
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000250
AC:
38
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.000915
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000496
Hom.:
0
Bravo
AF:
0.000332
ESP6500AA
AF:
0.000532
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000108
AC:
13

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 16, 2024- -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 11, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 06, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.49
Cadd
Benign
19
Dann
Uncertain
1.0
Eigen
Benign
-0.035
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.83
T;T;T;T;T;.;.
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.046
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L;L;.;L;L;L;L
MutationTaster
Benign
0.98
D;D;N;N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.80
N;N;.;N;N;.;.
REVEL
Benign
0.082
Sift
Benign
0.14
T;T;.;T;T;.;.
Sift4G
Benign
0.33
T;T;T;T;T;T;T
Polyphen
0.023
.;.;.;.;B;.;.
Vest4
0.51
MutPred
0.53
Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);Gain of disorder (P = 0.0905);
MVP
0.31
MPC
0.14
ClinPred
0.053
T
GERP RS
5.7
Varity_R
0.18
gMVP
0.15

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: rs149471462; hg19: chr2-152537279; API