rs144180493

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001164507.2(NEB):c.5555T>G(p.Met1852Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,850 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1852V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 30 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 9.32

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01530838).

BP6

Variant 2-151663756-A-C is Benign according to our data. Variant chr2-151663756-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197524.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00331 (504/152302) while in subpopulation NFE AF = 0.0057 (388/68028). AF 95% confidence interval is 0.00524. There are 2 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.5555T>G	p.Met1852Arg	missense_variant	Exon 45 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.5555T>G	p.Met1852Arg	missense_variant	Exon 45 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.5555T>G	p.Met1852Arg	missense_variant	Exon 45 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.5555T>G	p.Met1852Arg	missense_variant	Exon 45 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.5555T>G	p.Met1852Arg	missense_variant	Exon 45 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

503

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00570

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00332

AC:

826

AN:

249030

AF XY:

0.00309

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000928

Gnomad NFE exome

AF:

0.00538

Gnomad OTH exome

AF:

0.00331

GnomAD4 exome

AF:

0.00526

AC:

7683

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

3745

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33464

American (AMR)

AF:

0.00244

AC:

109

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

101

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86256

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00631

AC:

7019

AN:

1111782

Other (OTH)

AF:

0.00404

AC:

244

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

469

939

1408

1878

2347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00331

AC:

504

AN:

152302

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

203

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

41574

American (AMR)

AF:

0.00229

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00570

AC:

388

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

110

137

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:

0.00521

Hom.:

Bravo

AF:

0.00344

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000504

AC:

ESP6500EA

AF:

0.00492

AC:

ExAC

AF:

0.00329

AC:

398

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Met1852Arg in exon 45 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (332/66652) of European chromo somes, including two homozygotes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs144180493).

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 07, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 16, 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.

not provided

Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BS2

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

Uncertain:1Benign:2

May 30, 2020

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 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;T;.;T;.;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;D;D;D;D;.;.

M_CAP

Benign

0.048

MetaRNN

Benign

0.015

T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.6

M;M;.;M;M;M;M

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

D;D;.;D;D;.;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

D;T;.;T;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Vest4

0.86

ClinPred

0.026

GERP RS

5.5

Varity_R

0.89

gMVP

0.60

Mutation Taster

=99/1

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