rs6717213

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001164507.2(NEB):c.10707G>A(p.Lys3569Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0391 in 1,613,874 control chromosomes in the GnomAD database, including 3,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 1073 hom., cov: 31)

Exomes 𝑓: 0.034 ( 2567 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.97

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 2-151619616-C-T is Benign according to our data. Variant chr2-151619616-C-T is described in ClinVar as Benign. ClinVar VariationId is 129762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.10707G>A	p.Lys3569Lys	synonymous_variant	Exon 73 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.10707G>A	p.Lys3569Lys	synonymous_variant	Exon 73 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.10707G>A	p.Lys3569Lys	synonymous_variant	Exon 73 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.10707G>A	p.Lys3569Lys	synonymous_variant	Exon 73 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.9978G>A	p.Lys3326Lys	synonymous_variant	Exon 70 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.0834

AC:

12685

AN:

152090

Hom.:

1058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0456

Gnomad ASJ

AF:

0.0639

Gnomad EAS

AF:

0.167

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0778

GnomAD2 exomes

AF:

0.0556

AC:

13836

AN:

248946

AF XY:

0.0561

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0214

Gnomad ASJ exome

AF:

0.0612

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.0153

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0409

GnomAD4 exome

AF:

0.0344

AC:

50338

AN:

1461666

Hom.:

2567

Cov.:

AF XY:

0.0363

AC XY:

26422

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.222

AC:

7446

AN:

33478

American (AMR)

AF:

0.0239

AC:

1067

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0640

AC:

1673

AN:

26136

East Asian (EAS)

AF:

0.166

AC:

6594

AN:

39690

South Asian (SAS)

AF:

0.112

AC:

9629

AN:

86256

European-Finnish (FIN)

AF:

0.0148

AC:

790

AN:

53402

Middle Eastern (MID)

AF:

0.0439

AC:

253

AN:

5768

European-Non Finnish (NFE)

AF:

0.0177

AC:

19680

AN:

1111844

Other (OTH)

AF:

0.0531

AC:

3206

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

2648

5297

7945

10594

13242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1026

2052

3078

4104

5130

<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:

0.0838

AC:

12756

AN:

152208

Hom.:

1073

Cov.:

AF XY:

0.0845

AC XY:

6290

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.210

AC:

8716

AN:

41498

American (AMR)

AF:

0.0455

AC:

696

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0639

AC:

222

AN:

3472

East Asian (EAS)

AF:

0.167

AC:

866

AN:

5172

South Asian (SAS)

AF:

0.123

AC:

595

AN:

4820

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1232

AN:

68024

Other (OTH)

AF:

0.0884

AC:

187

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

530

1060

1590

2120

2650

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0424

Hom.:

1689

Bravo

AF:

0.0897

Asia WGS

AF:

0.183

AC:

635

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0211

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys3569Lys in exon 73 of NEB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 19.7% (795/4026) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6717213). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Feb 18, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nemaline myopathy 2

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

5.0

Mutation Taster

=64/36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over