rs1057516758

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001164507.2(NEB):c.6078delA(p.Lys2026AsnfsTer62) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000697 in 1,435,286 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NEB
NM_001164507.2 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.05

Publications

0 publications found

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 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

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 2-151658087-GT-G is Pathogenic according to our data. Variant chr2-151658087-GT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 370777.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 link	c.6078delA	p.Lys2026AsnfsTer62	frameshift_variant, splice_region_variant	Exon 48 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.6078delA	p.Lys2026AsnfsTer62	frameshift_variant, splice_region_variant	Exon 48 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.6078delA	p.Lys2026AsnfsTer62	frameshift_variant, splice_region_variant	Exon 48 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.6078delA	p.Lys2026AsnfsTer62	frameshift_variant, splice_region_variant	Exon 48 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.6078delA	p.Lys2026AsnfsTer62	frameshift_variant, splice_region_variant	Exon 48 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435286

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32922

American (AMR)

AF:

0.0000231

AC:

AN:

43206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25780

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

83764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092244

Other (OTH)

AF:

0.00

AC:

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:3

Apr 12, 2016

Counsyl

Significance:Likely 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 11, 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.Lys2026Asnfs*62) 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). ClinVar contains an entry for this variant (Variation ID: 370777). For these reasons, this variant has been classified as Pathogenic. -

Aug 09, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Pathogenic:1

Jun 01, 2024

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

6.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over