rs56026241

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001164508.2(NEB):​c.21418-6delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 24355 hom., cov: 0)
Exomes 𝑓: 0.61 ( 264503 hom. )

Consequence

NEB
NM_001164508.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.54
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 Benign. Variant got -16 ACMG points.

BP6
Variant 2-151531901-AT-A is Benign according to our data. Variant chr2-151531901-AT-A is described in ClinVar as [Benign]. Clinvar id is 95112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151531901-AT-A is described in Lovd as [Benign]. Variant chr2-151531901-AT-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEBNM_001164507.2 linkc.21418-6delA splice_region_variant, intron_variant Intron 143 of 181 ENST00000427231.7 NP_001157979.2
NEBNM_001164508.2 linkc.21418-6delA splice_region_variant, intron_variant Intron 143 of 181 ENST00000397345.8 NP_001157980.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEBENST00000397345.8 linkc.21418-6delA splice_region_variant, intron_variant Intron 143 of 181 5 NM_001164508.2 ENSP00000380505.3 P20929-2
NEBENST00000427231.7 linkc.21418-6delA splice_region_variant, intron_variant Intron 143 of 181 5 NM_001164507.2 ENSP00000416578.2 P20929-3

Frequencies

GnomAD3 genomes
AF:
0.554
AC:
84079
AN:
151834
Hom.:
24334
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.384
Gnomad AMI
AF:
0.508
Gnomad AMR
AF:
0.681
Gnomad ASJ
AF:
0.510
Gnomad EAS
AF:
0.582
Gnomad SAS
AF:
0.403
Gnomad FIN
AF:
0.644
Gnomad MID
AF:
0.649
Gnomad NFE
AF:
0.625
Gnomad OTH
AF:
0.565
GnomAD3 exomes
AF:
0.591
AC:
127200
AN:
215382
Hom.:
38523
AF XY:
0.581
AC XY:
67119
AN XY:
115620
show subpopulations
Gnomad AFR exome
AF:
0.388
Gnomad AMR exome
AF:
0.724
Gnomad ASJ exome
AF:
0.526
Gnomad EAS exome
AF:
0.583
Gnomad SAS exome
AF:
0.410
Gnomad FIN exome
AF:
0.639
Gnomad NFE exome
AF:
0.624
Gnomad OTH exome
AF:
0.610
GnomAD4 exome
AF:
0.607
AC:
858614
AN:
1414682
Hom.:
264503
Cov.:
0
AF XY:
0.601
AC XY:
422334
AN XY:
702968
show subpopulations
Gnomad4 AFR exome
AF:
0.382
Gnomad4 AMR exome
AF:
0.713
Gnomad4 ASJ exome
AF:
0.520
Gnomad4 EAS exome
AF:
0.627
Gnomad4 SAS exome
AF:
0.410
Gnomad4 FIN exome
AF:
0.640
Gnomad4 NFE exome
AF:
0.625
Gnomad4 OTH exome
AF:
0.590
GnomAD4 genome
AF:
0.554
AC:
84129
AN:
151952
Hom.:
24355
Cov.:
0
AF XY:
0.556
AC XY:
41269
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.385
Gnomad4 AMR
AF:
0.681
Gnomad4 ASJ
AF:
0.510
Gnomad4 EAS
AF:
0.581
Gnomad4 SAS
AF:
0.404
Gnomad4 FIN
AF:
0.644
Gnomad4 NFE
AF:
0.625
Gnomad4 OTH
AF:
0.558
Alfa
AF:
0.593
Hom.:
4866
Bravo
AF:
0.554
Asia WGS
AF:
0.450
AC:
1568
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Feb 03, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 05, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Feb 27, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: c.21523-6dupA in NEB gene is an intronic change that involves a mildly conserved nucleotide. 3/5 programs in Alamut predict that this variant does not have significant effect on the normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.6045 (49666 /82164chrs tested), including numerous homozygotes across multiple populations. The observed frequency exceed the maximum expected allele frequency for a pathogenic variant of 0.0035. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign by reputable databases/clinical laboratories. Considering all, the variant was classified as Benign. -

Feb 28, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:2
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nemaline Myopathy, Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs56026241; hg19: chr2-152388415; API