rs762278237

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001164508.2(NEB):​c.12018+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,601,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

NEB
NM_001164508.2 splice_donor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.82
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0041832826 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-151610515-C-T is Pathogenic according to our data. Variant chr2-151610515-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151610515-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-151610515-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEBNM_001164507.2 linkuse as main transcriptc.12018+1G>A splice_donor_variant ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkuse as main transcriptc.12018+1G>A splice_donor_variant ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkuse as main transcriptc.12018+1G>A splice_donor_variant 5 NM_001164508.2 ENSP00000380505 P5P20929-2
NEBENST00000427231.7 linkuse as main transcriptc.12018+1G>A splice_donor_variant 5 NM_001164507.2 ENSP00000416578 A2P20929-3
NEBENST00000409198.5 linkuse as main transcriptc.11289+1G>A splice_donor_variant 5 ENSP00000386259 P20929-4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248618
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134874
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000131
AC:
19
AN:
1449106
Hom.:
0
Cov.:
30
AF XY:
0.0000166
AC XY:
12
AN XY:
721770
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.0000154
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000332
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:4
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 03, 2021NM_001271208.1(NEB):c.12018+1G>A is a canonical splice variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. c.12018+1G>A has been observed in cases with relevant disease (PMID: 25205138). Functional assessments of this variant are not available in the literature. c.12018+1G>A has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_001271208.1(NEB):c.12018+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2023This sequence change affects a donor splice site in intron 80 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs762278237, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with autosomal recessive nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 265494). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Likely pathogenic, criteria provided, single submitterresearchBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardDec 03, 2018The heterozygous c.12018+1G>A variant in NEB was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nemaline myopathy. This variant has been reported in the compound heterozygous state, with a splice site variant and a frameshift variant, in two additional, unrelated individuals (PMID: 25205138). The presence of this variant in combination with a reported pathogenic variant and in several individual with nemaline myopathy increases the likelihood that the c.12018+1G>A variant is pathogenic. This variant has been identified in 0.002981% (1/33548) of Latino chromosomes and 0.001798% (2/111260) of European (non-Finnish) chromsomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762278237). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The c.12018+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to remove a splicing site, causing abnormal splicing that does not result in a frameshift in the reading frame. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, the c.12018+1G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3_Strong (Richards 2015). -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxDec 24, 2019Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); The c.12018+1 G>A variant has been reported previously in the presence of a second NEB variant, in two unrelated individual with nemaline myopathy, however, no other phenotypic or family information was available (Lehtokari et al., 2014); This variant is associated with the following publications: (PMID: 25205138, 31589614) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 21, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
D;D;D;D
GERP RS
5.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.37
Position offset: -3
DS_DL_spliceai
0.98
Position offset: 1

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: rs762278237; hg19: chr2-152467029; COSMIC: COSV51458885; API