NM_001164507.2:c.16637G>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.16637G>A(p.Arg5546His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5546C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 12 hom., cov: 19)

Exomes 𝑓: 0.0020 ( 589 hom. )

Failed GnomAD Quality Control

Consequence

NEB
NM_001164507.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.79

Publications

1 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=0.03037572).

BP6

Variant 2-151579405-C-T is Benign according to our data. Variant chr2-151579405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257765.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.16637G>A	p.Arg5546His	missense_variant	Exon 105 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.16637G>A	p.Arg5546His	missense_variant	Exon 105 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.16637G>A	p.Arg5546His	missense_variant	Exon 105 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.16637G>A	p.Arg5546His	missense_variant	Exon 105 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000413693.5 link	c.827G>A	p.Arg276His	missense_variant	Exon 5 of 74	5		ENSP00000410961.1	H0Y786
NEB	ENST00000409198.5 link	c.11602-3051G>A		intron_variant	Intron 78 of 149	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1669

AN:

136432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.00765

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.00453

Gnomad SAS

AF:

0.00490

Gnomad FIN

AF:

0.00752

Gnomad MID

AF:

0.0192

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.00966

GnomAD2 exomes

AF:

0.000925

AC:

143

AN:

154636

AF XY:

0.000770

show subpopulations

Gnomad AFR exome

AF:

0.00100

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000934

Gnomad FIN exome

AF:

0.000240

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00199

AC:

2701

AN:

1356718

Hom.:

589

Cov.:

AF XY:

0.00200

AC XY:

1336

AN XY:

669282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00162

AC:

AN:

30888

American (AMR)

AF:

0.00214

AC:

AN:

35126

Ashkenazi Jewish (ASJ)

AF:

0.000240

AC:

AN:

24968

East Asian (EAS)

AF:

0.00160

AC:

AN:

35006

South Asian (SAS)

AF:

0.000678

AC:

AN:

78146

European-Finnish (FIN)

AF:

0.00366

AC:

170

AN:

46496

Middle Eastern (MID)

AF:

0.000496

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.00206

AC:

2159

AN:

1046062

Other (OTH)

AF:

0.00232

AC:

130

AN:

55994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.247

Heterozygous variant carriers

242

483

725

966

1208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0122

AC:

1669

AN:

136554

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

734

AN XY:

66370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0127

AC:

491

AN:

38796

American (AMR)

AF:

0.00757

AC:

103

AN:

13606

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

3400

East Asian (EAS)

AF:

0.00454

AC:

AN:

4842

South Asian (SAS)

AF:

0.00490

AC:

AN:

4492

European-Finnish (FIN)

AF:

0.00752

AC:

AN:

8644

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0157

AC:

940

AN:

59694

Other (OTH)

AF:

0.00901

AC:

AN:

1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0189

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

Mar 29, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25203624) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Peripheral neuropathy

Uncertain:1

Aug 22, 2016

Claritas Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: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

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0089

.;T;.;T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.63

T;T;T;T;.;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.030

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

2.8

PROVEAN

Benign

-0.37

N;.;N;N;.;.

REVEL

Benign

0.054

Sift

Benign

0.64

T;.;T;T;.;.

Sift4G

Benign

0.12

T;T;T;T;T;T

Vest4

0.16

MVP

0.15

MPC

0.061

ClinPred

0.0063

GERP RS

2.6

gMVP

0.020

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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