rs377452683

chr2-151727801-ATGCTGGCTGTGCCAG-Achr2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAGchr2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAGTGCTGGCTGTGCCAG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):c.169_183del(p.Leu57_Ala61del) variant causes a 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (53 hom.)
• Consequence: NEB NM_001164507.2 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_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 GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.169_183del	p.Leu57_Ala61del	inframe_deletion	5/182	ENST00000427231.7
NEB	NM_001164508.2	c.169_183del	p.Leu57_Ala61del	inframe_deletion	5/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.169_183del	p.Leu57_Ala61del	inframe_deletion	5/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.169_183del	p.Leu57_Ala61del	inframe_deletion	5/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.169_183del	p.Leu57_Ala61del	inframe_deletion	5/150	5

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152038 Hom.: 47 Cov.: 32

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.: 21 AF XY: 0.00432 AC XY: 581 AN XY: 134632

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.: 53 AF XY: 0.00327 AC XY: 2375 AN XY: 726068

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.: 47 Cov.: 32 AF XY: 0.0143 AC XY: 1067 AN XY: 74396

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.: 0

Bravo AF: 0.0157

EpiCase AF: 0.00202

EpiControl AF: 0.00214

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Eurofins Ntd Llc (ga)	Mar 11, 2013	- -
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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

NEB: PM4, BS1, BS2 -

Nemaline myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs377452683; hg19: chr2-152584315;