2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_001164507.2(NEB):c.169_183dupCTGGCACAGCCAGCA(p.Ala61_Ser62insLeuAlaGlnProAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,612,006 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A61A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

NEB
NM_001164507.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: -0.579

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 -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001164507.2

BP6

Variant 2-151727801-A-ATGCTGGCTGTGCCAG is Benign according to our data. Variant chr2-151727801-A-ATGCTGGCTGTGCCAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421412.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.169_183dupCTGGCACAGCCAGCA	p.Ala61_Ser62insLeuAlaGlnProAla	conservative_inframe_insertion	Exon 5 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.169_183dupCTGGCACAGCCAGCA	p.Ala61_Ser62insLeuAlaGlnProAla	conservative_inframe_insertion	Exon 5 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 link	c.169_183dupCTGGCACAGCCAGCA	p.Ala61_Ser62insLeuAlaGlnProAla	conservative_inframe_insertion	Exon 5 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.169_183dupCTGGCACAGCCAGCA	p.Ala61_Ser62insLeuAlaGlnProAla	conservative_inframe_insertion	Exon 5 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.169_183dupCTGGCACAGCCAGCA	p.Ala61_Ser62insLeuAlaGlnProAla	conservative_inframe_insertion	Exon 5 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000145

AC:

AN:

248352

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000709

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1459840

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726092

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33456

American (AMR)

AF:

0.0000448

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26128

East Asian (EAS)

AF:

0.00169

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000818

AC:

AN:

85612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

1110910

Other (OTH)

AF:

0.000431

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000105

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41524

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5180

South Asian (SAS)

AF:

0.000210

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000800

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nemaline myopathy 2

Uncertain:2

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.169_183dup, results in the insertion of 5 amino acid(s) of the NEB protein (p.Leu57_Ala61dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770886969, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 421412). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Jan 17, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Oct 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NEB c.169_183dup15 (p.Leu57_Ala61dup) results in an in-frame duplication that is predicted to duplicate 5 amino acids into the encoded protein. The variant allele was found at a frequency of 0.00014 in 248352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00014 vs 0.0035), allowing no conclusion about variant significance. c.169_183dup15 has been reported in the literature in compound heterozygous individuals affected with Nemaline Myopathy 2 or Multiple Congenital Contractures (Wang_2020, Turgut_2024)). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38278647, 32222963). ClinVar contains an entry for this variant (Variation ID: 421412). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Oct 22, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32222963) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: PM4, BP4 -

Congenital structural myopathy

Uncertain:1

Nov 22, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Arthrogryposis multiplex congenita 6

Uncertain:1

Jan 10, 2022

Istanbul Faculty of Medicine, Istanbul University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.58

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAG

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