rs35686968

Variant names:

Variant summary

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

The NM_001164507.2(NEB):c.571G>C(p.Glu191Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,012 control chromosomes in the GnomAD database, including 553 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 0.016 ( 44 hom., cov: 31)

Exomes 𝑓: 0.024 ( 509 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 7.49

Publications

16 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=0.010740876).

BP6

Variant 2-151724301-C-G is Benign according to our data. Variant chr2-151724301-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129748.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2429/152182) while in subpopulation NFE AF = 0.0259 (1759/68010). AF 95% confidence interval is 0.0249. There are 44 homozygotes in GnomAd4. There are 1148 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.571G>C	p.Glu191Gln	missense_variant	Exon 8 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.571G>C	p.Glu191Gln	missense_variant	Exon 8 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.571G>C	p.Glu191Gln	missense_variant	Exon 8 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.571G>C	p.Glu191Gln	missense_variant	Exon 8 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.571G>C	p.Glu191Gln	missense_variant	Exon 8 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2429

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00488

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00976

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.0163

AC:

4051

AN:

248062

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00408

Gnomad AMR exome

AF:

0.00531

Gnomad ASJ exome

AF:

0.00409

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0215

Gnomad NFE exome

AF:

0.0256

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0239

AC:

34883

AN:

1460830

Hom.:

509

Cov.:

AF XY:

0.0236

AC XY:

17122

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.00341

AC:

114

AN:

33466

American (AMR)

AF:

0.00587

AC:

262

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00394

AC:

103

AN:

26114

East Asian (EAS)

AF:

0.000101

AC:

AN:

39684

South Asian (SAS)

AF:

0.0105

AC:

902

AN:

86036

European-Finnish (FIN)

AF:

0.0213

AC:

1139

AN:

53360

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0280

AC:

31106

AN:

1111462

Other (OTH)

AF:

0.0204

AC:

1229

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1556

3111

4667

6222

7778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0160

AC:

2429

AN:

152182

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1148

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00486

AC:

202

AN:

41524

American (AMR)

AF:

0.0111

AC:

170

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00977

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0210

AC:

222

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1759

AN:

68010

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0233

Hom.:

Bravo

AF:

0.0142

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.00503

AC:

ESP6500EA

AF:

0.0255

AC:

212

ExAC

AF:

0.0163

AC:

1974

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2018

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NEB c.571G>C (p.Glu191Gln) results in a conservative amino acid change located in the Nebulin repeat region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.016 in 276052 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 4.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.571G>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites variant as "benign." Based on the evidence outlined above, the variant was classified as benign. -

May 31, 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nemaline myopathy 2

Benign:4

Jun 08, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

not provided

Uncertain:1Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BS1, BS2 -

Aug 23, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

MetaRNN

Benign

0.011

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

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.6

L;L;.;L;L;L;L

PhyloP100

7.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.2

N;N;.;N;N;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.19

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.72

MPC

0.34

ClinPred

0.013

GERP RS

6.0

Varity_R

0.34

gMVP

0.56

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