2-151499299-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_001164508.2(NEB):​c.24113C>A​(p.Ser8038*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,463,804 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

NEB
NM_001164508.2 stop_gained

Scores

4
2
1
Splicing: ADA: 0.9817
2

Clinical Significance

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

Conservation

PhyloP100: 8.12
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 Pathogenic. Variant got 19 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
Variant 2-151499299-G-T is Pathogenic according to our data. Variant chr2-151499299-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151499299-G-T is described in Lovd as [Pathogenic]. Variant chr2-151499299-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.24113C>A p.Ser8038* stop_gained Exon 169 of 182 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.24113C>A p.Ser8038* stop_gained Exon 169 of 182 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.24113C>A p.Ser8038* stop_gained Exon 169 of 182 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.24113C>A p.Ser8038* stop_gained Exon 169 of 182 5 NM_001164507.2 ENSP00000416578.2 P20929-3

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151870
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:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000363
AC:
5
AN:
137924
Hom.:
0
AF XY:
0.0000137
AC XY:
1
AN XY:
72990
show subpopulations
Gnomad AFR exome
AF:
0.000141
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:
0.0000733
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000358
AC:
47
AN:
1311934
Hom.:
0
Cov.:
20
AF XY:
0.0000339
AC XY:
22
AN XY:
649108
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000443
Gnomad4 OTH exome
AF:
0.0000365
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
151870
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74174
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:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000679
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

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

Submissions by phenotype

not provided Pathogenic:2
Jun 04, 2021
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed multiple times with another NEB variant in patients with nemaline myopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Wallgren-Pettersson et al., 2004; Lehtokari et al., 2014; Levesque et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 15336686, 25205138, 26809612, 26809617, 16917880) -

Jun 04, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2, PM3, PS4_moderate, PVS1 -

Nemaline myopathy 2 Pathogenic:2
Mar 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser8073*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 15336686, 26809617). This variant is also known as Ser8038Ter and stop codon in exon 170. ClinVar contains an entry for this variant (Variation ID: 496134). For these reasons, this variant has been classified as Pathogenic. -

Apr 06, 2017
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nemaline myopathy Pathogenic:1
May 08, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: NEB c.24218C>A (p.Ser8073X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 138376 control chromosomes. c.24218C>A has been reported in the literature in individuals affected with Nemaline Myopathy 2 and subsequently cited by others (example, Levesque_2016, Lehtokari_2006, Lehtokari_2014, Wallgren-Pettersson_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Arthrogryposis multiplex congenita 6 Pathogenic:1
Mar 20, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
59
DANN
Uncertain
0.98
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.96
D
Vest4
0.95
GERP RS
6.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.77
SpliceAI score (max)
0.16
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: rs1458048713; hg19: chr2-152355813; API