2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_001164507.2(NEB):c.183_184insCTGGCACAGCCAGCA(p.Leu57_Ala61dup) variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: NEB NM_001164507.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.579

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.183_184insCTGGCACAGCCAGCA	p.Leu57_Ala61dup	inframe_insertion	5/182	ENST00000427231.7
NEB	NM_001164508.2	c.183_184insCTGGCACAGCCAGCA	p.Leu57_Ala61dup	inframe_insertion	5/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.183_184insCTGGCACAGCCAGCA	p.Leu57_Ala61dup	inframe_insertion	5/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.183_184insCTGGCACAGCCAGCA	p.Leu57_Ala61dup	inframe_insertion	5/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.183_184insCTGGCACAGCCAGCA	p.Leu57_Ala61dup	inframe_insertion	5/150	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152048 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 248352 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134632

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 SAS exome AF: 0.0000332

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.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 726092

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0000818

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000882

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74400

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	NEB: PM4, BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2019	This variant is associated with the following publications: (PMID: 32222963) -

Arthrogryposis multiplex congenita 6 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Istanbul Faculty of Medicine, Istanbul University

Jan 10, 2022

- -

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;