rs398124172

Positions:

• chr2-151643268-GCTCGTTTATTT-G

Variant summary

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

The NM_001164507.2(NEB):​c.8031_8041del​(p.Lys2677AsnfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,574 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: 0.000010 (0 hom.)
• Consequence: NEB NM_001164507.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.86

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 2-151643268-GCTCGTTTATTT-G is Pathogenic according to our data. Variant chr2-151643268-GCTCGTTTATTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 95138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151643268-GCTCGTTTATTT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.8031_8041del	p.Lys2677AsnfsTer7	frameshift_variant	58/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.8031_8041del	p.Lys2677AsnfsTer7	frameshift_variant	58/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.8031_8041del	p.Lys2677AsnfsTer7	frameshift_variant	58/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.8031_8041del	p.Lys2677AsnfsTer7	frameshift_variant	58/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.8031_8041del	p.Lys2677AsnfsTer7	frameshift_variant	58/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461574 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727066

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2023	This sequence change creates a premature translational stop signal (p.Lys2677Asnfs*7) 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 premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 16917880, 25205138). This variant is also known as g.89878_89888delAAATAAACGAG, Lys2677fs. ClinVar contains an entry for this variant (Variation ID: 95138). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2015	- -

Nemaline myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 29, 2022

Variant summary: NEB c.8031_8041del11 (p.Lys2677AsnfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249094 control chromosomes (gnomAD). c.8031_8041del11 has been reported in the literature in at least three compound heterozygous individuals affected with Nemaline Myopathy (Lehtokari_2006, Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 18, 2017

- -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398124172; hg19: chr2-152499782;