chr2-151656478-A-T

Variant names:

Variant summary

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

The ENST00000397345.8(NEB):c.6184-14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,568,950 control chromosomes in the GnomAD database, including 4,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1373 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2882 hom. )

Consequence

NEB
ENST00000397345.8 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0720

Publications

8 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:

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=-0.81).

BP6

Variant 2-151656478-A-T is Benign according to our data. Variant chr2-151656478-A-T is described in ClinVar as Benign. ClinVar VariationId is 226846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397345.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NEB	NM_001164507.2	MANE Plus Clinical	c.6184-14T>A	intron	N/A	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.6184-14T>A	intron	N/A	NP_001157980.2
NEB	NM_001271208.2		c.6184-14T>A	intron	N/A	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.6184-14T>A	intron	N/A	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6184-14T>A	intron	N/A	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.6184-14T>A	intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15447

AN:

152022

Hom.:

1370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0602

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0499

Gnomad SAS

AF:

0.0550

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0532

Gnomad OTH

AF:

0.0903

GnomAD2 exomes

AF:

0.0598

AC:

14166

AN:

236936

AF XY:

0.0576

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0331

Gnomad ASJ exome

AF:

0.0909

Gnomad EAS exome

AF:

0.0448

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0522

Gnomad OTH exome

AF:

0.0565

GnomAD4 exome

AF:

0.0558

AC:

79013

AN:

1416810

Hom.:

2882

Cov.:

AF XY:

0.0552

AC XY:

38661

AN XY:

700956

show subpopulations

African (AFR)

AF:

0.231

AC:

7497

AN:

32466

American (AMR)

AF:

0.0361

AC:

1557

AN:

43158

Ashkenazi Jewish (ASJ)

AF:

0.0927

AC:

2284

AN:

24648

East Asian (EAS)

AF:

0.0518

AC:

2036

AN:

39286

South Asian (SAS)

AF:

0.0528

AC:

4165

AN:

78850

European-Finnish (FIN)

AF:

0.0158

AC:

824

AN:

52278

Middle Eastern (MID)

AF:

0.0772

AC:

432

AN:

5596

European-Non Finnish (NFE)

AF:

0.0521

AC:

56341

AN:

1082062

Other (OTH)

AF:

0.0663

AC:

3877

AN:

58466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3713

7426

11138

14851

18564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2308

4616

6924

9232

11540

<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:

0.102

AC:

15470

AN:

152140

Hom.:

1373

Cov.:

AF XY:

0.0977

AC XY:

7264

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.233

AC:

9674

AN:

41460

American (AMR)

AF:

0.0600

AC:

916

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

367

AN:

3472

East Asian (EAS)

AF:

0.0496

AC:

257

AN:

5182

South Asian (SAS)

AF:

0.0545

AC:

263

AN:

4828

European-Finnish (FIN)

AF:

0.0122

AC:

130

AN:

10616

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0533

AC:

3622

AN:

68004

Other (OTH)

AF:

0.0894

AC:

189

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

660

1320

1979

2639

3299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0397

Hom.:

Bravo

AF:

0.111

Asia WGS

AF:

0.0840

AC:

294

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nemaline myopathy 2 (3)

not specified (3)

not provided (2)

Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.2

(source)

DANN

Benign

0.54

PhyloP100

-0.072

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over