rs1553564693

Variant names:

• chr2-151687649-CT-C
• rs1553564693
• NM_001164507.2:c.2499delA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164508.2(NEB):​c.2499delA​(p.Ala834ProfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEB NM_001164508.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.802

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 2-151687649-CT-C is Pathogenic according to our data. Variant chr2-151687649-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.2499delA	p.Ala834ProfsTer9	frameshift_variant	Exon 26 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.2499delA	p.Ala834ProfsTer9	frameshift_variant	Exon 26 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.2499delA	p.Ala834ProfsTer9	frameshift_variant	Exon 26 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.2499delA	p.Ala834ProfsTer9	frameshift_variant	Exon 26 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.2499delA	p.Ala834ProfsTer9	frameshift_variant	Exon 26 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459908 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726086

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:2

Nov 11, 2023

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.Ala834Profs*9) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 435967). For these reasons, this variant has been classified as Pathogenic. -

Jul 11, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1553564693; hg19: chr2-152544163;