rs200731870

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001164507.2(NEB):c.25336C>T(p.Arg8446*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R8446R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

NEB
NM_001164507.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.79

Publications

2 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 2-151490039-G-A is Pathogenic according to our data. Variant chr2-151490039-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 449500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	NM_001164507.2	MANE Plus Clinical	c.25336C>T	p.Arg8446*	stop_gained	Exon 181 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.25336C>T	p.Arg8446*	stop_gained	Exon 181 of 182	NP_001157980.2
NEB	NM_001271208.2		c.25441C>T	p.Arg8481*	stop_gained	Exon 182 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.25336C>T	p.Arg8446*	stop_gained	Exon 181 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25336C>T	p.Arg8446*	stop_gained	Exon 181 of 182	ENSP00000416578.2
RIF1	ENST00000457745.1	TSL:1	n.480+3283G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000322

AC:

AN:

248620

AF XY:

0.0000371

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461094

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111532

Other (OTH)

AF:

0.0000166

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.605

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000372

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Pathogenic:4

Oct 17, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in the literature as a c.25441C>T (p.Arg8481Ter) change in an alternate transcript (NM_001271208.1). This nonsense variant found in exon 181 of 182 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in NEB is an established mechanism of disease (PMID: 25205138). This variant has been previously reported as a compound heterozygous change in patients with nemaline myopathy (PMID: 25205138, 30057997). The c.25336C>T (p.Arg8446Ter) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.003% (43/1613188) and thus is presumed to be rare. Based on the available evidence, c.25336C>T (p.Arg8446Ter) is classified as Pathogenic.

Feb 02, 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.

Oct 07, 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.Arg8481*) 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 (rs200731870, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 449500). For these reasons, this variant has been classified as Pathogenic.

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Pathogenic:2

Sep 30, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a family with nemaline myopathy who also harbored a NEB frameshift variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Lehtokari et al., 2014); 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30467404, 25205138, 30057997, 34426522, 31589614, 31127727)

Nov 18, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline myopathy

Pathogenic:1

Jan 13, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NEB c.25441C>T (p.Arg8481X) 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. The variant allele was found at a frequency of 3.2e-05 in 248620 control chromosomes. c.25441C>T has been reported in the literature in at-least two individuals affected with Nemaline Myopathy (Lehtokari_2014) and congenital core-rod myopathy (Wunderlich_2018) respectively. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Arthrogryposis multiplex congenita 6

Pathogenic:1

Feb 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.85

PhyloP100

2.8

Vest4

0.85

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=1/199

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over