Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.18693G>C(p.Ala6231Ala) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,611,602 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 38 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Splicing: ADA: 0.9982

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.63

Publications

1 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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 2-151563606-C-G is Benign according to our data. Variant chr2-151563606-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00481 (733/152292) while in subpopulation EAS AF = 0.0454 (235/5178). AF 95% confidence interval is 0.0406. There are 11 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

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.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	NP_001157980.2
NEB	NM_001271208.2		c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.18693G>C	p.Ala6231Ala	synonymous	Exon 119 of 182	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.13590G>C	p.Ala4530Ala	splice_region synonymous	Exon 92 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0461

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00619

AC:

1541

AN:

248958

AF XY:

0.00578

show subpopulations

Gnomad AFR exome

AF:

0.00846

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0494

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00186

AC:

2720

AN:

1459310

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1332

AN XY:

726140

show subpopulations

African (AFR)

AF:

0.00907

AC:

303

AN:

33398

American (AMR)

AF:

0.00997

AC:

446

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.0314

AC:

1245

AN:

39692

South Asian (SAS)

AF:

0.00365

AC:

315

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000982

AC:

109

AN:

1109708

Other (OTH)

AF:

0.00484

AC:

292

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

172

344

515

687

859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00481

AC:

733

AN:

152292

Hom.:

Cov.:

AF XY:

0.00509

AC XY:

379

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00924

AC:

384

AN:

41552

American (AMR)

AF:

0.00490

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0454

AC:

235

AN:

5178

South Asian (SAS)

AF:

0.00436

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

109

146

182

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:

0.00163

Hom.:

Bravo

AF:

0.00589

Asia WGS

AF:

0.0170

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Nemaline myopathy 2 (3)

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

7.6

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.15

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