rs12998234

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001164507.2(NEB):c.12667G>A(p.Ala4223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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. A4223A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 5 hom., cov: 14)

Exomes 𝑓: 0.0018 ( 560 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.999

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004699439).

BP6

Variant 2-151606686-C-T is Benign according to our data. Variant chr2-151606686-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12667G>A	p.Ala4223Thr	missense_variant	Exon 84 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12667G>A	p.Ala4223Thr	missense_variant	Exon 84 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12667G>A	p.Ala4223Thr	missense_variant	Exon 84 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12667G>A	p.Ala4223Thr	missense_variant	Exon 84 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+3123G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

232

AN:

96318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.00159

Gnomad FIN

AF:

0.000436

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000475

Gnomad OTH

AF:

0.000799

GnomAD2 exomes

AF:

0.00437

AC:

400

AN:

91562

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.00444

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0373

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00308

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00184

AC:

1560

AN:

849434

Hom.:

560

Cov.:

AF XY:

0.00192

AC XY:

813

AN XY:

422800

show subpopulations

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

African (AFR)

AF:

0.00193

AC:

AN:

30114

American (AMR)

AF:

0.000948

AC:

AN:

17924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19290

East Asian (EAS)

AF:

0.0467

AC:

998

AN:

21372

South Asian (SAS)

AF:

0.00146

AC:

AN:

63540

European-Finnish (FIN)

AF:

0.00433

AC:

AN:

20558

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

2766

European-Non Finnish (NFE)

AF:

0.000371

AC:

236

AN:

636188

Other (OTH)

AF:

0.00172

AC:

AN:

37682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00241

AC:

232

AN:

96438

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

114

AN XY:

46080

show subpopulations

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

African (AFR)

AF:

0.00445

AC:

162

AN:

36384

American (AMR)

AF:

0.00103

AC:

AN:

6776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2584

East Asian (EAS)

AF:

0.0125

AC:

AN:

2952

South Asian (SAS)

AF:

0.00159

AC:

AN:

3142

European-Finnish (FIN)

AF:

0.000436

AC:

AN:

4590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000475

AC:

AN:

37890

Other (OTH)

AF:

0.000784

AC:

AN:

1276

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.289

Heterozygous variant carriers

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:

0.00582

Hom.:

ExAC

AF:

0.00229

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely 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). This variant represents a nonhomologous position within the three repet itive blocks (c.12667G, c.14125A, and c.15583A). The variable alleles at this po sition are not expected to have clinical significance due to a lack of conservat ion across species, including mammals. A change at this position has also been i dentified in 0.33% (22/6658) of Asian chromosomes by the Exome Aggregate Consort ium (http://exac.broadinstitute.org/). -

PreventionGenetics, part of Exact Sciences

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

- -

Jan 19, 2018

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:2

Aug 28, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6

Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

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_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.2

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.015

.;T;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.48

T;T;T;.;.

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-1.0

PROVEAN

Benign

-0.95

N;.;N;.;.

REVEL

Benign

0.045

Sift

Benign

0.40

T;.;T;.;.

Sift4G

Uncertain

0.032

D;D;D;D;D

Vest4

0.12

MutPred

0.58

Gain of methylation at K4218 (P = 0.072);Gain of methylation at K4218 (P = 0.072);Gain of methylation at K4218 (P = 0.072);Gain of methylation at K4218 (P = 0.072);Gain of methylation at K4218 (P = 0.072);

MVP

0.31

MPC

0.31

ClinPred

0.025

GERP RS

3.1

gMVP

0.00061

Mutation Taster

=99/1

polymorphism (auto)

(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