2-151485783-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001164507.2(NEB):​c.25555G>A​(p.Ala8519Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,611,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.91
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]
RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.25555G>A p.Ala8519Thr missense_variant 182/182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.25555G>A p.Ala8519Thr missense_variant 182/182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.25555G>A p.Ala8519Thr missense_variant 182/1825 NM_001164508.2 ENSP00000380505 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.25555G>A p.Ala8519Thr missense_variant 182/1825 NM_001164507.2 ENSP00000416578 A2P20929-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
247914
Hom.:
0
AF XY:
0.0000372
AC XY:
5
AN XY:
134344
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:
0.0000446
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000521
AC:
76
AN:
1459680
Hom.:
0
Cov.:
31
AF XY:
0.0000524
AC XY:
38
AN XY:
725714
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
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:
0.0000630
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000566
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000331
AC:
4
EpiCase
AF:
0.000274
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 26, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 25, 2022This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8554 of the NEB protein (p.Ala8554Thr). This variant is present in population databases (rs775823432, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 653358). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 04, 2022The c.19987G>A (p.A6663T) alteration is located in exon 150 (coding exon 148) of the NEB gene. This alteration results from a G to A substitution at nucleotide position 19987, causing the alanine (A) at amino acid position 6663 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 08, 2019Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.038
.;.;T;.;T;T;.;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;.;.
M_CAP
Benign
0.085
D
MetaRNN
Pathogenic
0.75
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
1.1
L;.;.;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.5
D;N;.;N;D;N;.;.
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;D;.;D;D;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D
Polyphen
0.0020
.;.;.;.;B;.;.;.
Vest4
0.69
MutPred
0.59
Gain of catalytic residue at A6663 (P = 0.0446);.;.;.;Gain of catalytic residue at A6663 (P = 0.0446);.;.;.;
MVP
0.60
MPC
0.34
ClinPred
0.94
D
GERP RS
5.5
Varity_R
0.67
gMVP
0.53

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: rs775823432; hg19: chr2-152342297; API