rs199791504

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164507.2(NEB):c.20467-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 7 hom., cov: 0)

Exomes 𝑓: 0.013 ( 19 hom. )

Consequence

NEB
NM_001164507.2 splice_region, intron

Scores

Splicing: ADA: 0.00001815

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.613

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:

LOC124906081 (HGNC:):

LOC124906081 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 2-151546002-A-T is Benign according to our data. Variant chr2-151546002-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.20467-4T>A		splice_region_variant, intron_variant	Intron 134 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.20467-4T>A		splice_region_variant, intron_variant	Intron 134 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.20467-4T>A		splice_region_variant, intron_variant	Intron 134 of 181	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.20467-4T>A		splice_region_variant, intron_variant	Intron 134 of 181	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.0424

AC:

1237

AN:

29190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.0431

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0158

Gnomad FIN

AF:

0.0287

Gnomad MID

AF:

0.109

Gnomad NFE

AF:

0.0843

Gnomad OTH

AF:

0.0585

GnomAD2 exomes

AF:

0.0957

AC:

2496

AN:

26088

AF XY:

0.0966

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.0632

Gnomad EAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0710

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.150

GnomAD4 exome

AF:

0.0128

AC:

8846

AN:

693182

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

4541

AN XY:

345514

show subpopulations

African (AFR)

AF:

0.00440

AC:

AN:

8870

American (AMR)

AF:

0.0106

AC:

217

AN:

20564

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

199

AN:

10854

East Asian (EAS)

AF:

0.000401

AC:

AN:

19966

South Asian (SAS)

AF:

0.00699

AC:

221

AN:

31600

European-Finnish (FIN)

AF:

0.00605

AC:

158

AN:

26102

Middle Eastern (MID)

AF:

0.0275

AC:

AN:

2834

European-Non Finnish (NFE)

AF:

0.0139

AC:

7557

AN:

544852

Other (OTH)

AF:

0.0134

AC:

369

AN:

27540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

340

680

1019

1359

1699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.0424

AC:

1238

AN:

29192

Hom.:

Cov.:

AF XY:

0.0423

AC XY:

593

AN XY:

14016

show subpopulations

African (AFR)

AF:

0.00847

AC:

110

AN:

12984

American (AMR)

AF:

0.103

AC:

189

AN:

1830

Ashkenazi Jewish (ASJ)

AF:

0.0431

AC:

AN:

904

East Asian (EAS)

AF:

0.00

AC:

AN:

714

South Asian (SAS)

AF:

0.0166

AC:

AN:

1386

European-Finnish (FIN)

AF:

0.0287

AC:

AN:

1012

Middle Eastern (MID)

AF:

0.114

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0844

AC:

815

AN:

9658

Other (OTH)

AF:

0.0570

AC:

AN:

386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

115

173

230

288

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00961

Hom.:

Bravo

AF:

0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 14, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 10, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nemaline myopathy 2

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.074

(source)

DANN

Benign

0.42

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0040

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over