2-151727801-ATGCTGGCTGTGCCAG-A

Position:

chr2-151727801-ATGCTGGCTGTGCCAG-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001164508.2(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. 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_001164508.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001164508.2

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. Variant chr2-151727801-ATGCTGGCTGTGCCAG-A is described in Lovd as [Likely_pathogenic].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2 linkuse as main transcript	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	5/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	5/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	5/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	5/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.169_183delCTGGCACAGCCAGCA	p.Leu57_Ala61del	conservative_inframe_deletion	5/150	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

GnomAD3 exomes

AF:

0.00520

AC:

1291

AN:

248352

Hom.:

AF XY:

0.00432

AC XY:

581

AN XY:

134632

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 SAS exome

AF:

0.000199

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

Gnomad4 AFR exome

AF:

0.0484

Gnomad4 AMR exome

AF:

0.00424

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000269

Gnomad4 FIN exome

AF:

0.00412

Gnomad4 NFE exome

AF:

0.00245

Gnomad4 OTH exome

AF:

0.00486

GnomAD4 genome

AF:

0.0146

AC:

2222

AN:

152156

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1067

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0448

Gnomad4 AMR

AF:

0.00674

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000419

Gnomad4 FIN

AF:

0.00537

Gnomad4 NFE

AF:

0.00251

Gnomad4 OTH

AF:

0.0104

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

NEB: PM4, BP4, BS1, BS2 -

Nemaline myopathy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over