2-151576297-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001164507.2(NEB):c.16762T>A(p.Ser5588Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0153 in 1,609,038 control chromosomes in the GnomAD database, including 1,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S5588S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 308 hom., cov: 30)

Exomes 𝑓: 0.013 ( 900 hom. )

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.01

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019331276).

BP6

Variant 2-151576297-A-T is Benign according to our data. Variant chr2-151576297-A-T is described in ClinVar as Benign. ClinVar VariationId is 129710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.16762T>A	p.Ser5588Thr	missense_variant	Exon 106 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.16762T>A	p.Ser5588Thr	missense_variant	Exon 106 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.16762T>A	p.Ser5588Thr	missense_variant	Exon 106 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.16762T>A	p.Ser5588Thr	missense_variant	Exon 106 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11659T>A	p.Ser3887Thr	missense_variant	Exon 79 of 150	5		ENSP00000386259.1	P20929-4
NEB	ENST00000413693.5 link	c.952T>A	p.Ser318Thr	missense_variant	Exon 6 of 74	5		ENSP00000410961.1	H0Y786

Frequencies

GnomAD3 genomes

AF:

0.0378

AC:

5700

AN:

150874

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0318

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.0740

Gnomad FIN

AF:

0.0000971

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00196

Gnomad OTH

AF:

0.0383

GnomAD2 exomes

AF:

0.0282

AC:

7005

AN:

248574

AF XY:

0.0286

show subpopulations

Gnomad AFR exome

AF:

0.0979

Gnomad AMR exome

AF:

0.00587

Gnomad ASJ exome

AF:

0.0325

Gnomad EAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0129

AC:

18880

AN:

1458050

Hom.:

900

Cov.:

AF XY:

0.0143

AC XY:

10365

AN XY:

725402

show subpopulations

African (AFR)

AF:

0.102

AC:

3427

AN:

33444

American (AMR)

AF:

0.00620

AC:

277

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

843

AN:

26066

East Asian (EAS)

AF:

0.139

AC:

5515

AN:

39662

South Asian (SAS)

AF:

0.0653

AC:

5605

AN:

85840

European-Finnish (FIN)

AF:

0.000357

AC:

AN:

53248

Middle Eastern (MID)

AF:

0.0148

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00147

AC:

1629

AN:

1109200

Other (OTH)

AF:

0.0246

AC:

1480

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

828

1656

2484

3312

4140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.0380

AC:

5736

AN:

150988

Hom.:

308

Cov.:

AF XY:

0.0383

AC XY:

2824

AN XY:

73740

show subpopulations

African (AFR)

AF:

0.0982

AC:

4033

AN:

41062

American (AMR)

AF:

0.0154

AC:

233

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

110

AN:

3464

East Asian (EAS)

AF:

0.149

AC:

763

AN:

5128

South Asian (SAS)

AF:

0.0744

AC:

356

AN:

4782

European-Finnish (FIN)

AF:

0.0000971

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00196

AC:

133

AN:

67822

Other (OTH)

AF:

0.0480

AC:

100

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

243

487

730

974

1217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0140

Hom.:

Bravo

AF:

0.0402

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.0941

AC:

358

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.0307

AC:

3706

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Nov 26, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser5588Thr in exon 106 of NEB: This variant is not expected to have clinical s ignificance because it has been identified in 9.4% (358/3806) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs35227368). -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 04, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 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. -

Nemaline myopathy 2

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

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

PhyloP100

5.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.20

Sift

Uncertain

0.011

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

Sift4G

Benign

0.089

T;D;D;D;T;D;D;D

Polyphen

0.98

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

Vest4

0.41

MPC

0.33

ClinPred

0.037

GERP RS

5.9

Varity_R

0.30

gMVP

0.65

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