2-151527004-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_001164507.2(NEB):​c.21859C>T​(p.Arg7287Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,597,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7287G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

2
8
9

Clinical Significance

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

Conservation

PhyloP100: 3.29
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-151527004-G-A is Benign according to our data. Variant chr2-151527004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2337296.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEBNM_001164507.2 linkuse as main transcriptc.21859C>T p.Arg7287Trp missense_variant 148/182 ENST00000427231.7
NEBNM_001164508.2 linkuse as main transcriptc.21859C>T p.Arg7287Trp missense_variant 148/182 ENST00000397345.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.21859C>T p.Arg7287Trp missense_variant 148/1825 NM_001164508.2 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.21859C>T p.Arg7287Trp missense_variant 148/1825 NM_001164507.2 A2P20929-3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000223
AC:
5
AN:
224598
Hom.:
0
AF XY:
0.0000414
AC XY:
5
AN XY:
120738
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000620
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:
0.0000303
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000159
AC:
23
AN:
1445532
Hom.:
0
Cov.:
30
AF XY:
0.0000195
AC XY:
14
AN XY:
717298
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000465
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:
0.0000172
Gnomad4 OTH exome
AF:
0.0000335
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.0000332
AC:
4

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 19, 2022The c.16756C>T (p.R5586W) alteration is located in exon 121 (coding exon 119) of the NEB gene. This alteration results from a C to T substitution at nucleotide position 16756, causing the arginine (R) at amino acid position 5586 to be replaced by a tryptophan (W). 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, RevvityMar 08, 2019- -
Nemaline myopathy 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 16, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
.;.;T;.;T;T;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;.;.
M_CAP
Benign
0.028
D
MetaRNN
Uncertain
0.52
D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.92
L;.;.;.;L;.;.;.
MutationTaster
Benign
0.99
D;D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.9
D;D;.;D;D;D;.;.
REVEL
Benign
0.25
Sift
Benign
0.15
T;T;.;D;T;D;.;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.;.
Vest4
0.57
MVP
0.60
MPC
0.35
ClinPred
0.87
D
GERP RS
5.1
Varity_R
0.22
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs376072545; hg19: chr2-152383518; COSMIC: COSV51467543; COSMIC: COSV51467543; API