rs200427401

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7BS1BP4

This summary comes from the ClinGen Evidence Repository: The c.11067C>T is a synonymous (silent) variant (p.Asn3689=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0006878 (922/1461502 alleles, 2 homozygotes) in the non-Finnish European population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive congenital myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: BS1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1908888/MONDO:0018958/146

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

NEB
NM_001164507.2 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.92

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 -6 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	Exon 74 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	Exon 74 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NEB	ENST00000397345.8 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	Exon 74 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7 link	c.11067C>T	p.Asn3689Asn	synonymous_variant	Exon 74 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5 link	c.10338C>T	p.Asn3446Asn	synonymous_variant	Exon 71 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000450

AC:

112

AN:

248706

AF XY:

0.000511

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.000675

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000631

AC:

922

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

447

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33470

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000162

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000730

AC:

811

AN:

1111698

Other (OTH)

AF:

0.000712

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000427

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000564

Hom.:

Bravo

AF:

0.000276

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: BP4, BP7 -

Jul 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NEB-related disorder

Benign:1

Aug 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy

Benign:1

Aug 07, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.11067C>T is a synonymous (silent) variant (p.Asn3689=) that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v4.1.0 is 0.0006878 (922/1461502 alleles, 2 homozygotes) in the non-Finnish European population, which is higher than the ClinGen Congenital Myopathies VCEP threshold (MAF ≥ 0.000237) for BS1, and therefore meets this criterion (BS1). In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive congenital myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathy VCEP: BS1, BP4, BP7. (Congenital Myopathies VCEP specifications version 1; 8/7/2024) -

Nemaline myopathy 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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_noAF

Benign

-0.74

CADD

Benign

3.5

(source)

DANN

Benign

0.65

PhyloP100

-1.9

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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