NM_001164507.2:c.23989C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001164507.2(NEB):c.23989C>T(p.Arg7997*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,548,396 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

NEB
NM_001164507.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:2

Conservation

PhyloP100: 0.865

Publications

3 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: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-151501423-G-A is Pathogenic according to our data. Variant chr2-151501423-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373977.

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.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	NP_001157980.2
NEB	NM_001271208.2		c.24094C>T	p.Arg8032*	stop_gained	Exon 169 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENSP00000416578.2
NEB	ENST00000688578.1		c.772C>T	p.Arg258*	stop_gained	Exon 9 of 21	ENSP00000509628.1

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000272

AC:

AN:

157874

AF XY:

0.000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

Gnomad ASJ exome

AF:

0.000234

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000237

Gnomad NFE exome

AF:

0.000470

Gnomad OTH exome

AF:

0.00159

GnomAD4 exome

AF:

0.000310

AC:

433

AN:

1396230

Hom.:

Cov.:

AF XY:

0.000335

AC XY:

231

AN XY:

688560

show subpopulations

African (AFR)

AF:

0.0000951

AC:

AN:

31546

American (AMR)

AF:

0.0000841

AC:

AN:

35660

Ashkenazi Jewish (ASJ)

AF:

0.000120

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

35796

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78496

European-Finnish (FIN)

AF:

0.000793

AC:

AN:

49174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000339

AC:

365

AN:

1076946

Other (OTH)

AF:

0.000329

AC:

AN:

57838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

103

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:

0.000302

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41514

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000286

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.000218

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 2 (8)

not provided (8)

Nemaline myopathy (2)

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (2)

Arthrogryposis multiplex congenita 6 (1)

Muscular dystrophy;C0030196:Limb pain;C1836156:Progressive proximal muscle weakness (1)

NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.88

PhyloP100

0.86

Vest4

0.76

ClinPred

0.35

GERP RS

-2.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: -32

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

Computational scores

Splicing

Publications

Other links and lift over