rs200125713

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001164507.2(NEB):c.13628A>C(p.Lys4543Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K4543K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.17 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.551

Publications

0 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 (MetaRNN=0.0024766624).

BP6

Variant 2-151600602-T-G is Benign according to our data. Variant chr2-151600602-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.13628A>C	p.Lys4543Thr	missense_variant	Exon 89 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.13628A>C	p.Lys4543Thr	missense_variant	Exon 89 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.13628A>C	p.Lys4543Thr	missense_variant	Exon 89 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.13628A>C	p.Lys4543Thr	missense_variant	Exon 89 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+9207A>C		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AC:

AN:

Hom.:

Cov.:

GnomAD2 exomes

AF:

0.204

AC:

2030

AN:

9974

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.0879

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.192

Gnomad OTH exome

AF:

0.186

GnomAD4 exome

AF:

0.165

AC:

2415

AN:

14614

Hom.:

Cov.:

AF XY:

0.164

AC XY:

1330

AN XY:

8092

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0786

AC:

AN:

140

American (AMR)

AF:

0.224

AC:

500

AN:

2230

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

AN:

132

East Asian (EAS)

AF:

0.219

AC:

136

AN:

620

South Asian (SAS)

AF:

0.114

AC:

296

AN:

2592

European-Finnish (FIN)

AF:

0.131

AC:

AN:

282

Middle Eastern (MID)

AF:

0.0625

AC:

AN:

European-Non Finnish (NFE)

AF:

0.165

AC:

1331

AN:

8054

Other (OTH)

AF:

0.161

AC:

AN:

548

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

Heterozygous variant carriers

144

288

433

577

721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

Data not reliable, filtered out with message: AC0;AS_VQSR

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

Alfa

AF:

0.0525

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 23, 2018

GeneDx

Significance:Likely 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. -

Feb 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 82, 90, and 98) are co-amplified and sequenced (each amplicon consists of 6 a lleles). Due to this method, we are unable to determine in which repetitive bloc k this variant occurs [c.13628A>C (p.Lys4543Thr) in exon 89; c.15086A>C (pLys502 9Thr) in exon 97; c.16544A>C (p.Lys5515Thr) in exon 105]. This variant is not ex pected to have clinical significance because it has been identified in 34.4% (10 44/3038) chromosomes across several diverse populations by the Exome Aggregate C onsortium (http://exac.broadinstitute.org/variant/2-152436012-T-G). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.1

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.018

.;T;.;.;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.71

T;T;T;.;.

M_CAP

Benign

0.020

MetaRNN

Benign

0.0025

T;T;T;T;T

MetaSVM

Benign

-0.83

PhyloP100

-0.55

PROVEAN

Benign

-0.40

N;.;N;.;.

REVEL

Benign

0.076

Sift

Benign

0.030

D;.;D;.;.

Sift4G

Benign

0.063

T;T;T;T;T

Vest4

0.18

MutPred

0.51

Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);Loss of methylation at K4543 (P = 0.0124);

MPC

0.22

ClinPred

0.017

GERP RS

-3.3

gMVP

0.0034

Mutation Taster

=100/0

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over