rs532986882

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001164507.2(NEB):c.12688A>G(p.Ile4230Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 850,438 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4230R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 5 hom., cov: 14)

Exomes 𝑓: 0.000026 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: -8.08

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010523587).

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12688A>G	p.Ile4230Val	missense_variant	Exon 84 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12688A>G	p.Ile4230Val	missense_variant	Exon 84 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.12688A>G	p.Ile4230Val	missense_variant	Exon 84 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.12688A>G	p.Ile4230Val	missense_variant	Exon 84 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.11601+3144A>G		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

96772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000866

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000762

AC:

AN:

91882

AF XY:

0.0000200

show subpopulations

Gnomad AFR exome

AF:

0.000954

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000259

AC:

AN:

850438

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

423302

show subpopulations

African (AFR)

AF:

0.000591

AC:

AN:

30452

American (AMR)

AF:

0.00

AC:

AN:

17956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19294

East Asian (EAS)

AF:

0.00

AC:

AN:

21536

South Asian (SAS)

AF:

0.00

AC:

AN:

63638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2770

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

636436

Other (OTH)

AF:

0.000106

AC:

AN:

37756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000330

AC:

AN:

96890

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

AN XY:

46244

show subpopulations

African (AFR)

AF:

0.000863

AC:

AN:

37074

American (AMR)

AF:

0.00

AC:

AN:

6742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2572

East Asian (EAS)

AF:

0.00

AC:

AN:

2936

South Asian (SAS)

AF:

0.00

AC:

AN:

3158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

37754

Other (OTH)

AF:

0.00

AC:

AN:

1272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000253

Hom.:

ExAC

AF:

0.000323

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1Benign:1

Nov 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 11, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

NEB-related disorder

Uncertain:1

Sep 29, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NEB c.12688A>G variant is predicted to result in the amino acid substitution p.Ile4230Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.086% of alleles in individuals of African descent in gnomAD, including three homozygous individuals (http://gnomad.broadinstitute.org/variant/2-152463179-T-C). However, gnomAD warns that allele frequencies for this variant may be unreliable. This variant has been interpreted in ClinVar as both uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/534078). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

not provided

Uncertain:1

Feb 26, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0090

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0

.;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.77

T;T;T;.;.

M_CAP

Benign

0.0024

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

-8.1

PROVEAN

Benign

-0.16

N;.;N;.;.

REVEL

Benign

0.0040

Sift

Benign

0.046

D;.;D;.;.

Sift4G

Uncertain

0.017

D;D;D;D;D

Vest4

0.064

ClinPred

0.083

GERP RS

-7.9

gMVP

0.00052

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

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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