2-151633739-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001164508.2(NEB):​c.9329A>C​(p.Tyr3110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense

Scores

9
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.92
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.9329A>C p.Tyr3110Ser missense_variant Exon 65 of 182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.9329A>C p.Tyr3110Ser missense_variant Exon 65 of 182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.9329A>C p.Tyr3110Ser missense_variant Exon 65 of 182 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.9329A>C p.Tyr3110Ser missense_variant Exon 65 of 182 5 NM_001164507.2 ENSP00000416578.2 P20929-3
NEBENST00000409198.5 linkc.8854-2561A>C intron_variant Intron 62 of 149 5 ENSP00000386259.1 P20929-4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461702
Hom.:
0
Cov.:
113
AF XY:
0.00000275
AC XY:
2
AN XY:
727134
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:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.23
.;T;.;.;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;.;.
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Uncertain
-0.041
T
PROVEAN
Uncertain
-4.0
D;.;D;.;.
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D;.;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D
Vest4
0.84
MutPred
0.79
Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);
MVP
0.69
MPC
0.34
ClinPred
0.98
D
GERP RS
6.0
gMVP
0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-152490253; API