rs878854368

Variant names:

• chr2-151646139-GTTGA-G
• rs878854368
• NM_001164507.2:c.7523_7526delTCAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001164507.2(NEB):​c.7523_7526delTCAA​(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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-151646139-GTTGA-G is Pathogenic according to our data. Variant chr2-151646139-GTTGA-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 242434.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.7523_7526delTCAA	p.Ile2508ThrfsTer14	frameshift_variant	Exon 55 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.7523_7526delTCAA	p.Ile2508ThrfsTer14	frameshift_variant	Exon 55 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.7523_7526delTCAA	p.Ile2508ThrfsTer14	frameshift_variant	Exon 55 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.7523_7526delTCAA	p.Ile2508ThrfsTer14	frameshift_variant	Exon 55 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.7523_7526delTCAA	p.Ile2508ThrfsTer14	frameshift_variant	Exon 55 of 150	5		ENSP00000386259.1

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

GnomAD2 exomes AF: 0.0000186 AC: 4 AN: 214972 AF XY: 0.0000261

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33090

American (AMR) AF: 0.00 AC: 0 AN: 41346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38994

South Asian (SAS) AF: 0.00 AC: 0 AN: 81504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000210 AC: 23 AN: 1096592

Other (OTH) AF: 0.00 AC: 0 AN: 59390

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

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

May 29, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 06, 2024

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.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). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 16917880). This variant is also known as g.87012_87015del. ClinVar contains an entry for this variant (Variation ID: 242434). For these reasons, this variant has been classified as Pathogenic. -

NEB-related disorder Pathogenic:1

Nov 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 23, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 16, 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

Sep 02, 2021

Fulgent Genetics, Fulgent 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
PhyloP100		4.3
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854368; hg19: chr2-152502653;