2-151727817-TGCTGGCTGTGCCAGA-TGCTGGCTGTGCCAGAGCTGGCTGTGCCAGA

Position:

• chr2-151727817-TGCTGGCTGTGCCAGA-TGCTGGCTGTGCCAGAGCTGGCTGTGCCAGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001164508.2(NEB):​c.167_168insTCTGGCACAGCCAGC​(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 0.00114 in 1,604,630 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (14 hom.)
• Consequence: NEB NM_001164508.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.768

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001164508.2
• BP6: Variant 2-151727817-T-TGCTGGCTGTGCCAGA is Benign according to our data. Variant chr2-151727817-T-TGCTGGCTGTGCCAGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419871.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000622 (92/147970) while in subpopulation SAS AF= 0.0116 (56/4826). AF 95% confidence interval is 0.00918. There are 1 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.167_168insTCTGGCACAGCCAGC	p.Leu57_Ala61dup	inframe_insertion	5/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.167_168insTCTGGCACAGCCAGC	p.Leu57_Ala61dup	inframe_insertion	5/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.167_168insTCTGGCACAGCCAGC	p.Leu57_Ala61dup	inframe_insertion	5/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.167_168insTCTGGCACAGCCAGC	p.Leu57_Ala61dup	inframe_insertion	5/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.167_168insTCTGGCACAGCCAGC	p.Leu57_Ala61dup	inframe_insertion	5/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.000615 AC: 91 AN: 147858 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000729

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000325

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00154 AC: 379 AN: 246372 Hom.: 5 AF XY: 0.00197 AC XY: 264 AN XY: 133888

Gnomad AFR exome AF: 0.0000713

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000392

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.00119 AC: 1736 AN: 1456660 Hom.: 14 Cov.: 31 AF XY: 0.00147 AC XY: 1062 AN XY: 724714

Gnomad4 AFR exome AF: 0.0000622

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000645

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000622 AC: 92 AN: 147970 Hom.: 1 Cov.: 32 AF XY: 0.000760 AC XY: 55 AN XY: 72390

Gnomad4 AFR AF: 0.0000791

Gnomad4 AMR AF: 0.000728

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000325

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2017	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

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: rs757726895; hg19: chr2-152584331;