chr2-151663543-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001164508.2(NEB):c.5763+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,448,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NEB
NM_001164508.2 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:2

Conservation

PhyloP100: 7.75

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]

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-151663543-C-T is Pathogenic according to our data. Variant chr2-151663543-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151663543-C-T is described in Lovd as [Pathogenic]. Variant chr2-151663543-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.5763+5G>A		splice_region_variant, intron_variant	Intron 45 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.5763+5G>A		splice_region_variant, intron_variant	Intron 45 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.5763+5G>A	splice_region_variant, intron_variant	Intron 45 of 181	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.5763+5G>A	splice_region_variant, intron_variant	Intron 45 of 181	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.5763+5G>A	splice_region_variant, intron_variant	Intron 45 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000821

AC:

AN:

243460

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131980

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:

0.0000338

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000913

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000483

AC:

AN:

1448334

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718022

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:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000544

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

NEB-related disorder

Pathogenic:1Uncertain:1

Jul 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEB c.5763+5G>A variant is predicted to interfere with splicing. This variant was reported together with second NEB variant in at least one individual with typical Nemaline myopathy (Table S1C, Lehtokari et al. 2014. PubMed ID: 25205138; patient E2, Table 1, Cummings et al. 2017. PubMed ID: 28424332). This variant is predicted to alter splicing based on available splicing prediction software (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction softwares is not equivalent to functional evidence. This variant is reported in 0.0034% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Apr 10, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3 -

Nemaline myopathy 2

Pathogenic:1Uncertain:1

Jun 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Apr 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28424332). This sequence change falls in intron 45 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs776167256, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 25205138, 28424332; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as chr2:152520057C>T . ClinVar contains an entry for this variant (Variation ID: 552335). -

Nemaline myopathy

Pathogenic:1

Mar 18, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.5763+5G>A variant in NEB has been reported, in the compound heterozygous state, in one individual with nemaline myopathy (PMID: 25205138, 28424332), and has been identified in 0.002% (1/85046) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs776167256). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 552335) and has been interpreted as pathogenic by Invitae and as a variant of uncertain significance by Counsyl. This variant is located in the 3‚Äô splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. RNAseq analysis performed on affected tissue shows evidence of intron retention after exon 45 (PMID: 28424332). Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PM3, PVS1_strong, PM2_supporting (Richards 2015). -

Arthrogryposis multiplex congenita 6

Pathogenic:1

Mar 04, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: 5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over