rs377452683

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001164507.2(NEB):c.169_183delCTGGCACAGCCAGCA(p.Leu57_Ala61del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,611,950 control chromosomes in the GnomAD database, including 100 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 47 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 53 hom. )

Consequence

NEB
NM_001164507.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.20

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: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001164507.2

BP6

Variant 2-151727801-ATGCTGGCTGTGCCAG-A is Benign according to our data. Variant chr2-151727801-ATGCTGGCTGTGCCAG-A is described in ClinVar as [Benign]. Clinvar id is 95115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2222/152156) while in subpopulation AFR AF = 0.0448 (1859/41514). AF 95% confidence interval is 0.0431. There are 47 homozygotes in GnomAd4. There are 1067 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2 link	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 link	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	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_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 link	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 link	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	Exon 5 of 150	5		ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2219

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00537

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00520

AC:

1291

AN:

248352

AF XY:

0.00432

show subpopulations

Gnomad AFR exome

AF:

0.0468

Gnomad AMR exome

AF:

0.00410

Gnomad ASJ exome

AF:

0.000895

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00423

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.00352

AC:

5136

AN:

1459794

Hom.:

AF XY:

0.00327

AC XY:

2375

AN XY:

726068

show subpopulations

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

African (AFR)

AF:

0.0484

AC:

1618

AN:

33428

American (AMR)

AF:

0.00424

AC:

189

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000269

AC:

AN:

85612

European-Finnish (FIN)

AF:

0.00412

AC:

220

AN:

53392

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00245

AC:

2718

AN:

1110896

Other (OTH)

AF:

0.00486

AC:

293

AN:

60278

⚠️ 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: 0.399

Heterozygous variant carriers

272

543

815

1086

1358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0146

AC:

2222

AN:

152156

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1067

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0448

AC:

1859

AN:

41514

American (AMR)

AF:

0.00674

AC:

103

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000419

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00537

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00251

AC:

171

AN:

68016

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.0157

EpiCase

AF:

0.00202

EpiControl

AF:

0.00214

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 20, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NEB c.169_183del15 (p.Leu57_Ala61del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. The variant allele was found at a frequency of 0.0052 in 248352 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is benign. Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Dec 05, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 11, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: PM4, BP4, BS1, BS2 -

Nemaline myopathy 2

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=200/0

polymorphism

(source)

Splicing

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

Publications

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rs377452683

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