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.16542C>G(p.Ala5514Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,492,632 control chromosomes in the GnomAD database, including 923 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 103 hom., cov: 15)

Exomes 𝑓: 0.0097 ( 820 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 1.16

Publications

2 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=-0.53).

BP6

Variant 2-151579500-G-C is Benign according to our data. Variant chr2-151579500-G-C is described in ClinVar as Benign. ClinVar VariationId is 257763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 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.16542C>G	p.Ala5514Ala	synonymous	Exon 105 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.16542C>G	p.Ala5514Ala	synonymous	Exon 105 of 182	NP_001157980.2
NEB	NM_001271208.2		c.16542C>G	p.Ala5514Ala	synonymous	Exon 105 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.16542C>G	p.Ala5514Ala	synonymous	Exon 105 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.16542C>G	p.Ala5514Ala	synonymous	Exon 105 of 182	ENSP00000416578.2
NEB	ENST00000413693.5	TSL:5	c.732C>G	p.Ala244Ala	synonymous	Exon 5 of 74	ENSP00000410961.1

Frequencies

GnomAD3 genomes

AF:

0.0189

AC:

2319

AN:

122916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0345

Gnomad EAS

AF:

0.157

Gnomad SAS

AF:

0.0529

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0142

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.0288

GnomAD2 exomes

AF:

0.0316

AC:

1928

AN:

60978

AF XY:

0.0331

show subpopulations

Gnomad AFR exome

AF:

0.0330

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.0406

Gnomad EAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.000243

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.00973

AC:

13325

AN:

1369628

Hom.:

820

Cov.:

AF XY:

0.0109

AC XY:

7359

AN XY:

676484

show subpopulations

African (AFR)

AF:

0.0315

AC:

992

AN:

31464

American (AMR)

AF:

0.00376

AC:

134

AN:

35626

Ashkenazi Jewish (ASJ)

AF:

0.0330

AC:

829

AN:

25140

East Asian (EAS)

AF:

0.137

AC:

4868

AN:

35628

South Asian (SAS)

AF:

0.0473

AC:

3737

AN:

78962

European-Finnish (FIN)

AF:

0.000286

AC:

AN:

48880

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

4054

European-Non Finnish (NFE)

AF:

0.00148

AC:

1559

AN:

1052796

Other (OTH)

AF:

0.0201

AC:

1147

AN:

57078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

541

1082

1622

2163

2704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.0191

AC:

2347

AN:

123004

Hom.:

103

Cov.:

AF XY:

0.0199

AC XY:

1159

AN XY:

58346

show subpopulations

African (AFR)

AF:

0.0302

AC:

1109

AN:

36686

American (AMR)

AF:

0.0115

AC:

120

AN:

10474

Ashkenazi Jewish (ASJ)

AF:

0.0345

AC:

108

AN:

3126

East Asian (EAS)

AF:

0.158

AC:

641

AN:

4066

South Asian (SAS)

AF:

0.0537

AC:

199

AN:

3704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7054

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.00194

AC:

107

AN:

55192

Other (OTH)

AF:

0.0373

AC:

AN:

1580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0121

Hom.:

Bravo

AF:

0.0185

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Nemaline myopathy 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

4.5

(source)

DANN

Benign

0.41

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

rs200602229

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