rs182847302

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_001164507.2(NEB):c.19455G>A(p.Lys6485Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,752 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 25 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.38

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 -12 ACMG points.

BP4

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

BP6

Variant 2-151553999-C-T is Benign according to our data. Variant chr2-151553999-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95110.

BP7

Synonymous conserved (PhyloP=1.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00418 (637/152218) while in subpopulation AMR AF = 0.00745 (114/15296). AF 95% confidence interval is 0.00634. There are 6 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.19455G>A	p.Lys6485Lys	synonymous_variant	Exon 126 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.19455G>A	p.Lys6485Lys	synonymous_variant	Exon 126 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8 link	c.19455G>A	p.Lys6485Lys	synonymous_variant	Exon 126 of 182	5	NM_001164508.2	ENSP00000380505.3		P20929-2
NEB	ENST00000427231.7 link	c.19455G>A	p.Lys6485Lys	synonymous_variant	Exon 126 of 182	5	NM_001164507.2	ENSP00000416578.2		P20929-3

Frequencies

GnomAD3 genomes

AF:

0.00419

AC:

637

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00746

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00488

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00401

AC:

999

AN:

248902

AF XY:

0.00427

show subpopulations

Gnomad AFR exome

AF:

0.000969

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00309

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0129

Gnomad NFE exome

AF:

0.00402

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00426

AC:

6231

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

3097

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33476

American (AMR)

AF:

0.00407

AC:

182

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86248

European-Finnish (FIN)

AF:

0.0120

AC:

641

AN:

53402

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00444

AC:

4936

AN:

1111734

Other (OTH)

AF:

0.00331

AC:

200

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

301

602

904

1205

1506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.00418

AC:

637

AN:

152218

Hom.:

Cov.:

AF XY:

0.00476

AC XY:

354

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41534

American (AMR)

AF:

0.00745

AC:

114

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00488

AC:

332

AN:

68010

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00356

Hom.:

Bravo

AF:

0.00304

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27641504) -

Oct 09, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4, BP7, BS2 -

Nemaline myopathy 2

Uncertain:1Benign:2

Nov 11, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

7.8

(source)

DANN

Benign

0.62

PhyloP100

1.4

Mutation Taster

=97/3

polymorphism

(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

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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