rs11902616

Variant names:

Variant summary

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

The NM_001164508.2(NEB):c.12018+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,540,414 control chromosomes in the GnomAD database, including 6,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2289 hom., cov: 32)

Exomes 𝑓: 0.039 ( 3809 hom. )

Consequence

NEB
NM_001164508.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.494

Publications

4 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
autosomal dominant nebulin-related myopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-151610487-C-T is Benign according to our data. Variant chr2-151610487-C-T is described in ClinVar as Benign. ClinVar VariationId is 257726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEB	NM_001164507.2	MANE Plus Clinical	c.12018+29G>A	intron	N/A	NP_001157979.2	P20929-3
NEB	NM_001164508.2	MANE Select	c.12018+29G>A	intron	N/A	NP_001157980.2	P20929-2
NEB	NM_001271208.2		c.12018+29G>A	intron	N/A	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEB	ENST00000397345.8	TSL:5 MANE Select	c.12018+29G>A	intron	N/A	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12018+29G>A	intron	N/A	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5	TSL:5	c.11289+29G>A	intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

17374

AN:

151940

Hom.:

2268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.315

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0572

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0994

GnomAD2 exomes

AF:

0.0659

AC:

16298

AN:

247142

AF XY:

0.0654

show subpopulations

Gnomad AFR exome

AF:

0.327

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0614

Gnomad EAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.0180

Gnomad OTH exome

AF:

0.0484

GnomAD4 exome

AF:

0.0393

AC:

54577

AN:

1388356

Hom.:

3809

Cov.:

AF XY:

0.0414

AC XY:

28766

AN XY:

694708

show subpopulations

African (AFR)

AF:

0.339

AC:

10784

AN:

31786

American (AMR)

AF:

0.0282

AC:

1257

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.0639

AC:

1637

AN:

25600

East Asian (EAS)

AF:

0.168

AC:

6592

AN:

39294

South Asian (SAS)

AF:

0.133

AC:

11208

AN:

84498

European-Finnish (FIN)

AF:

0.0148

AC:

791

AN:

53302

Middle Eastern (MID)

AF:

0.0514

AC:

288

AN:

5598

European-Non Finnish (NFE)

AF:

0.0177

AC:

18465

AN:

1045862

Other (OTH)

AF:

0.0614

AC:

3555

AN:

57880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2507

5015

7522

10030

12537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1014

2028

3042

4056

5070

<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:

0.115

AC:

17460

AN:

152058

Hom.:

2289

Cov.:

AF XY:

0.114

AC XY:

8491

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.316

AC:

13077

AN:

41414

American (AMR)

AF:

0.0571

AC:

872

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

221

AN:

3468

East Asian (EAS)

AF:

0.167

AC:

863

AN:

5172

South Asian (SAS)

AF:

0.146

AC:

705

AN:

4826

European-Finnish (FIN)

AF:

0.0166

AC:

176

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1247

AN:

67986

Other (OTH)

AF:

0.110

AC:

232

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

655

1310

1966

2621

3276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.0511

Hom.:

863

Bravo

AF:

0.126

Asia WGS

AF:

0.215

AC:

745

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arthrogryposis multiplex congenita 6 (1)

Nemaline myopathy 2 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.3

(source)

DANN

Benign

0.73

PhyloP100

-0.49

Mutation Taster

=99/1

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over