Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001164507.2(NEB):c.18294T>C(p.Tyr6098Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,590,154 control chromosomes in the GnomAD database, including 69,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5698 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63957 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.35

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 2-151565573-A-G is Benign according to our data. Variant chr2-151565573-A-G is described in ClinVar as Benign. ClinVar VariationId is 95108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.35 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

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.18294T>C	p.Tyr6098Tyr	synonymous	Exon 116 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.18294T>C	p.Tyr6098Tyr	synonymous	Exon 116 of 182	NP_001157980.2
NEB	NM_001271208.2		c.18294T>C	p.Tyr6098Tyr	synonymous	Exon 116 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.18294T>C	p.Tyr6098Tyr	synonymous	Exon 116 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18294T>C	p.Tyr6098Tyr	synonymous	Exon 116 of 182	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.13191T>C	p.Tyr4397Tyr	synonymous	Exon 89 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

38006

AN:

152078

Hom.:

5701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0873

Gnomad AMI

AF:

0.365

Gnomad AMR

AF:

0.392

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.287

AC:

69058

AN:

240454

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.0816

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.305

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.291

AC:

419159

AN:

1437958

Hom.:

63957

Cov.:

AF XY:

0.289

AC XY:

207051

AN XY:

715828

show subpopulations

African (AFR)

AF:

0.0775

AC:

2579

AN:

33262

American (AMR)

AF:

0.402

AC:

17518

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6638

AN:

25980

East Asian (EAS)

AF:

0.346

AC:

13647

AN:

39448

South Asian (SAS)

AF:

0.197

AC:

16796

AN:

85170

European-Finnish (FIN)

AF:

0.311

AC:

16503

AN:

53120

Middle Eastern (MID)

AF:

0.278

AC:

1591

AN:

5730

European-Non Finnish (NFE)

AF:

0.299

AC:

326842

AN:

1092054

Other (OTH)

AF:

0.286

AC:

17045

AN:

59596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

12529

25058

37588

50117

62646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10552

21104

31656

42208

52760

<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:

0.250

AC:

38005

AN:

152196

Hom.:

5698

Cov.:

AF XY:

0.252

AC XY:

18753

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0873

AC:

3627

AN:

41552

American (AMR)

AF:

0.392

AC:

5996

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

895

AN:

3472

East Asian (EAS)

AF:

0.321

AC:

1660

AN:

5174

South Asian (SAS)

AF:

0.198

AC:

956

AN:

4826

European-Finnish (FIN)

AF:

0.297

AC:

3138

AN:

10582

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20745

AN:

67988

Other (OTH)

AF:

0.268

AC:

568

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1387

2774

4162

5549

6936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.286

Hom.:

19998

Bravo

AF:

0.252

Asia WGS

AF:

0.214

AC:

749

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Nemaline myopathy 2 (4)

not provided (2)

Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.6

(source)

DANN

Benign

0.61

PhyloP100

1.3

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_001164507.2:c.18294T>C

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