NM_001164507.2:c.12770G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001164507.2(NEB):c.12770G>A(p.Arg4257His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict 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. R4257C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 8)

Exomes 𝑓: 0.00043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.25

Publications

3 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=0.009276062).

BP6

Variant 2-151604849-C-T is Benign according to our data. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194. Variant chr2-151604849-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 509194.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.12770G>A	p.Arg4257His	missense_variant	Exon 85 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.12770G>A	p.Arg4257His	missense_variant	Exon 85 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.12770G>A	p.Arg4257His	missense_variant	Exon 85 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.12770G>A	p.Arg4257His	missense_variant	Exon 85 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.11601+4960G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

170

AN:

61412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00280

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00714

Gnomad NFE

AF:

0.0000582

Gnomad OTH

AF:

0.00407

GnomAD2 exomes

AF:

0.00147

AC:

AN:

50432

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.000445

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000433

AC:

192

AN:

443338

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

AN XY:

233412

show subpopulations

African (AFR)

AF:

0.0129

AC:

131

AN:

10194

American (AMR)

AF:

0.000738

AC:

AN:

17622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11584

East Asian (EAS)

AF:

0.0000452

AC:

AN:

22112

South Asian (SAS)

AF:

0.0000917

AC:

AN:

43638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22574

Middle Eastern (MID)

AF:

0.000608

AC:

AN:

1644

European-Non Finnish (NFE)

AF:

0.0000515

AC:

AN:

291428

Other (OTH)

AF:

0.00120

AC:

AN:

22542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00277

AC:

170

AN:

61474

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

AN XY:

28658

show subpopulations

African (AFR)

AF:

0.0123

AC:

152

AN:

12326

American (AMR)

AF:

0.00279

AC:

AN:

4662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1704

East Asian (EAS)

AF:

0.00

AC:

AN:

1886

South Asian (SAS)

AF:

0.00

AC:

AN:

1480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0000582

AC:

AN:

34368

Other (OTH)

AF:

0.00402

AC:

AN:

746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ExAC

AF:

0.00104

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:1Benign:1

Nov 04, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with NEB-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 11, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 23, 2020

GeneDx

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

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.029

.;T;.;.;.

Eigen

Benign

0.010

Eigen_PC

Benign

-0.00082

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D;D;.;.

MetaRNN

Benign

0.0093

T;T;T;T;T

MetaSVM

Benign

-0.80

PhyloP100

3.3

PROVEAN

Benign

-1.1

N;.;N;.;.

REVEL

Benign

0.12

Sift

Benign

0.055

T;.;T;.;.

Sift4G

Uncertain

0.0030

D;D;D;D;D

Vest4

0.36

MutPred

0.50

Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);Loss of MoRF binding (P = 0.0232);

MVP

0.69

MPC

0.34

ClinPred

0.043

GERP RS

3.2

gMVP

0.0023

Mutation Taster

=92/8

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