rs878854368

chr2-151646139-GTTGA-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.7523_7526del(p.Ile2508ThrfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000151 in 1,586,504 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NEB NM_001164507.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.26

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 2-151646139-GTTGA-G is Pathogenic according to our data. Variant chr2-151646139-GTTGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151646139-GTTGA-G is described in Lovd as [Pathogenic]. Variant chr2-151646139-GTTGA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.7523_7526del	p.Ile2508ThrfsTer14	frameshift_variant	55/182	ENST00000427231.7
NEB	NM_001164508.2	c.7523_7526del	p.Ile2508ThrfsTer14	frameshift_variant	55/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.7523_7526del	p.Ile2508ThrfsTer14	frameshift_variant	55/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.7523_7526del	p.Ile2508ThrfsTer14	frameshift_variant	55/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.7523_7526del	p.Ile2508ThrfsTer14	frameshift_variant	55/150	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

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: 0.0000186 AC: 4 AN: 214972 Hom.: 0 AF XY: 0.0000261 AC XY: 3 AN XY: 115086

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000424

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 23 AN: 1434296 Hom.: 0 AF XY: 0.0000197 AC XY: 14 AN XY: 710900

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: 0.0000210

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

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

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 242434). This variant is also known as g.87012_87015del. This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 16917880). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ile2508Thrfs*14) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 29, 2018	- -

NEB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2022

The NEB c.7523_7526delTCAA variant is predicted to result in a frameshift and premature protein termination (p.Ile2508Thrfs*14). In the literature, this variant is also referred to as g.87012_87015delAATC. This variant has been reported in the compound heterozygous state in individuals with nemaline myopathy (Family 41, mild form of disease, Lehtokari et al. 2006. PubMed ID: 16917880; #17, Punetha et al. 2016. PubMed ID: 27854218). This variant was also reported in the heterozygous state in an induvial with nemaline myopathy (Family 19, Todd et al. 2015. PubMed ID: 26578207). This variant is reported in 0.0042% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152502653-GTTGA-G). Frameshift variants in NEB are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2017

The c.7523_7526delTCAA pathogenic variant in the NEB gene has been reported previously using alternate nomenclature (g.87012_87015delAATC) in combination with another NEB variant in an individual with a mild form of nemaline myopathy (Lehtokari et al., 2006). The c.7523_7526delTCAA variant causes a frameshift starting with codon Isoleucine 2508, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ile2508ThrfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.7523_7526delTCAA variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.7523_7526delTCAA as a pathogenic variant. -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2023

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854368; hg19: chr2-152502653;