2-151493859-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001164507.2(NEB):c.24588C>G(p.Tyr8196*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000899 in 1,557,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000093 ( 0 hom. )

Consequence

NEB
NM_001164507.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.26

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 links:

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 2-151493859-G-C is Pathogenic according to our data. Variant chr2-151493859-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 432817.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.24588C>G	p.Tyr8196*	stop_gained	Exon 175 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.24588C>G	p.Tyr8196*	stop_gained	Exon 175 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.24588C>G	p.Tyr8196*	stop_gained	Exon 175 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.24588C>G	p.Tyr8196*	stop_gained	Exon 175 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

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:

0.0000221

AC:

AN:

180836

AF XY:

0.0000417

show subpopulations

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:

0.0000517

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000925

AC:

AN:

1405200

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

694806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31764

American (AMR)

AF:

0.0000279

AC:

AN:

35862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24944

East Asian (EAS)

AF:

0.00

AC:

AN:

38396

South Asian (SAS)

AF:

0.00

AC:

AN:

77954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1081244

Other (OTH)

AF:

0.00

AC:

AN:

58294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000836

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:4

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.Tyr8231*) 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 (rs754272530, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 29382405). This variant is also known as c.24588C>G (p.Tyr8196*). ClinVar contains an entry for this variant (Variation ID: 432817). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Tyr8196Ter variant in NEB was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with nemaline myopathy. The presence of this variant in combination with a likely pathogenic variant and in an individual with nemaline myopathy increases the likelihood that the p.Tyr8196Ter variant is pathogenic. This variant has been identified in 0.005516% (5/90638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754272530). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 8196, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, this variant meets criteria to be classified as pathogenic for nemaline myopathy an autosomal recessive manner based on the predicted impact of the variant and occurrence with a likely pathogenic in an individual with nemaline myopathy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015). -

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 09, 2017

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. -

not provided

Pathogenic:1

Sep 13, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second pathogenic variant in two siblings affected with congenital myopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29382405); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34758253, 29382405) -

Arthrogryposis multiplex congenita 6

Pathogenic:1

Dec 26, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

PhyloP100

6.3

Vest4

0.95

ClinPred

1.0

GERP RS

5.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: 8

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

Publications

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2-151493859-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over