2-151662138-G-T

Variant summary

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

The NM_001164508.2(NEB):​c.5967C>A​(p.Asn1989Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,608,920 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

9
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.18
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 2 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.5967C>A p.Asn1989Lys missense_variant Exon 46 of 182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.5967C>A p.Asn1989Lys missense_variant Exon 46 of 182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.5967C>A p.Asn1989Lys missense_variant Exon 46 of 182 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.5967C>A p.Asn1989Lys missense_variant Exon 46 of 182 5 NM_001164507.2 ENSP00000416578.2 P20929-3
NEBENST00000409198.5 linkc.5967C>A p.Asn1989Lys missense_variant Exon 46 of 150 5 ENSP00000386259.1 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152028
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:
0.00000808
AC:
2
AN:
247428
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134234
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1456892
Hom.:
0
Cov.:
30
AF XY:
0.0000152
AC XY:
11
AN XY:
724676
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:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000307
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152028
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74234
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
ExAC
AF:
0.00000828
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
.;.;T;.;T;.;.
Eigen
Benign
0.12
Eigen_PC
Benign
0.028
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;.;.
M_CAP
Benign
0.074
D
MetaRNN
Uncertain
0.71
D;D;D;D;D;D;D
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.3
M;M;.;M;M;M;M
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.5
D;D;.;D;D;.;.
REVEL
Benign
0.27
Sift
Uncertain
0.012
D;D;.;D;D;.;.
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;D
Polyphen
0.97
.;.;.;.;D;.;.
Vest4
0.59
MutPred
0.77
Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);Gain of ubiquitination at N1989 (P = 0.0289);
MVP
0.58
MPC
0.31
ClinPred
0.86
D
GERP RS
2.1
Varity_R
0.26
gMVP
0.63

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: rs371151246; hg19: chr2-152518652; API