chr2-151561203-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001164508.2(NEB):c.19101+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000437 in 1,600,868 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NEB
NM_001164508.2 splice_region, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 3.87

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 12 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 2-151561203-C-T is Pathogenic according to our data. Variant chr2-151561203-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151561203-C-T is described in Lovd as [Pathogenic]. Variant chr2-151561203-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.19101+5G>A		splice_region_variant, intron_variant	Intron 122 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.19101+5G>A		splice_region_variant, intron_variant	Intron 122 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.19101+5G>A		splice_region_variant, intron_variant	Intron 122 of 181	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.19101+5G>A		splice_region_variant, intron_variant	Intron 122 of 181	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000855

AC:

AN:

233944

Hom.:

AF XY:

0.00000791

AC XY:

AN XY:

126388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000306

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:

0.00000955

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1448718

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000462

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000851

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:3Uncertain:1

Mar 20, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 05, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 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 results in skipping of 122, but is expected to preserve the integrity of the reading-frame (PMID: 23826317). ClinVar contains an entry for this variant (Variation ID: 557295). This variant has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 23826317, 31230720; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 122 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nemaline myopathy

Pathogenic:2

Mar 07, 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.19101+5G>A variant in NEB has been identified in two individuals with arthrogryposis multiplex congenita or nemaline myopathy (PMID: 23826317, 31230720) and has been identified in 0.003% (2/58542) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374929094). 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: 557295) and has been interpreted as pathogenic/likely pathogenic by Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), Institut de G√©n√©tique et Biologie Mol√©culaire et Cellulaire, Invitae, Natera Inc., and Baylor Genetics, and as a variant of uncertain significance by Counsyl. Of the 2 affected individuals, one was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the c.19101+5G>A variant is pathogenic (Variation ID: 449501; PMID: 31230720). cDNA analysis performed on affected tissue shows exon skipping of exon 122 (PMID:23826317). Exon 122 (NM_001164508.2) is in-frame with 105 nucleotides or 35 codons. This variant is located in the 5‚Äô splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In-frame exon skipping of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. The phenotype of an individual heterozygous for this variant is highly specific for nemaline myopathy based on the presence of nemaline rods on a muscle biopsy consistent with disease (PMID: 23826317). One additional likely pathogenic variant, predicted to induce the same splicing effect as this variant, has been reported in ClinVar as being associated with nemaline myopathy, supporting that the c.19101+5G>A may be pathogenic (Variation ID: 2010427). 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: PVS1_moderate, PM3, PP4, PM2_supporting, PS1_supporting (Richards 2015). -

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3+PM1+PM2+PM3+PP3+PP4 -

Arthrogryposis multiplex congenita 6

Pathogenic:1

Mar 21, 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

-0.44

CADD

Benign

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.51

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