chr2-151729614-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM3

This summary comes from the ClinGen Evidence Repository: The c.78+1G>A variant in NEB occurs within the canonical splice donor site +1 of intron 4. It is expected to disrupt RNA splicing of in-frame exon 4 leading to loss of protein function and loss-of-function of NEB is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007461 (88/1179410) in non-Finnish European which does not meet the threshold for PM2_Supporting (≤ 0.0000559). This variant has been detected in more than four unrelated affected individuals with a second pathogenic variant (PM3_Very Strong, Internal lab contributor: Invitae, SCV001578888.4; PMID:25205138, 30859559). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Very Strong (Congenital Myopathies VCEP specifications version 1; 8/7/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1912012/MONDO:0018958/146

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

NEB
NM_001164508.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 3.89

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 10 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.78+1G>A		splice_donor_variant, intron_variant	Intron 4 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.78+1G>A		splice_donor_variant, intron_variant	Intron 4 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.78+1G>A	splice_donor_variant, intron_variant	Intron 4 of 181	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.78+1G>A	splice_donor_variant, intron_variant	Intron 4 of 181	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.78+1G>A	splice_donor_variant, intron_variant	Intron 4 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248816

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134988

show subpopulations

Gnomad AFR exome

AF:

0.0000647

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461018

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726822

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:

0.0000792

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:4

Dec 01, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001271208.1(NEB):c.78+1G>A is a canonical splice variant classified as pathogenic in the context of NEB-related nemaline myopathy. c.78+1G>A has been observed in cases with relevant disease (PMID: 25205138, 30859559). Functional assessments of this variant are not available in the literature. c.78+1G>A has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, NM_001271208.1(NEB):c.78+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. -

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 4 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 (rs778593702, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with nemaline myopathy (PMID: 19232495, 25205138). ClinVar contains an entry for this variant (Variation ID: 552018). 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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy

Pathogenic:2

Mar 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NEB c.78+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of NEB function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 248816 control chromosomes. c.78+1G>A has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Todd_2015, Lehtokari_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25205138, 26578207). ClinVar contains an entry for this variant (Variation ID: 552018). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.78+1G>A variant in NEB occurs within the canonical splice donor site +1 of intron 4. It is expected to disrupt RNA splicing of in-frame exon 4 leading to loss of protein function and loss-of-function of NEB is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00007461 (88/1179410) in non-Finnish European which does not meet the threshold for PM2_Supporting (≤ 0.0000559). This variant has been detected in more than four unrelated affected individuals with a second pathogenic variant (PM3_Very Strong, Internal lab contributor: Invitae, SCV001578888.4; PMID: 25205138, 30859559). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1_Strong, PM3_Very Strong (Congenital Myopathies VCEP specifications version 1; 8/7/2024). -

NEB-related disorder

Pathogenic:1

Dec 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEB c.78+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in patients with nemaline myopathy (Lehtokari et al. 2009. PubMed ID: 19232495; Pagnamenta et al. 2019. PubMed ID: 30859559; Lehtokari et al. 2014. PubMed ID: 25205138). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in NEB are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jun 02, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita 6

Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Pathogenic:1

Apr 12, 2024

Fulgent Genetics, Fulgent 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

0.50

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.82

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

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.

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