rs145127681

Positions:

• chr2-151561114-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.19102-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,568,874 control chromosomes in the GnomAD database, including 1,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (120 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1202 hom.)
• Consequence: NEB NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001807
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0410

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-151561114-G-A is Benign according to our data. Variant chr2-151561114-G-A is described in ClinVar as [Benign]. Clinvar id is 129717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151561114-G-A is described in Lovd as [Benign]. Variant chr2-151561114-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0286 (4355/152202) while in subpopulation NFE AF= 0.0412 (2800/68006). AF 95% confidence interval is 0.0399. There are 120 homozygotes in gnomad4. There are 2265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 120 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.19102-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.19102-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.19102-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.19102-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	ENSP00000416578	A2

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4354 AN: 152084 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0274 AC: 6398 AN: 233910 Hom.: 157 AF XY: 0.0279 AC XY: 3533 AN XY: 126560

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.00785

Gnomad ASJ exome AF: 0.00692

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.00370

Gnomad FIN exome AF: 0.0929

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0364 AC: 51578 AN: 1416672 Hom.: 1202 Cov.: 25 AF XY: 0.0355 AC XY: 25026 AN XY: 705314

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.00834

Gnomad4 ASJ exome AF: 0.00714

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00358

Gnomad4 FIN exome AF: 0.0853

Gnomad4 NFE exome AF: 0.0412

Gnomad4 OTH exome AF: 0.0287

GnomAD4 genome AF: 0.0286 AC: 4355 AN: 152202 Hom.: 120 Cov.: 32 AF XY: 0.0304 AC XY: 2265 AN XY: 74414

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0976

Gnomad4 NFE AF: 0.0412

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0330 Hom.: 53

Bravo AF: 0.0204

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2021	Variant summary: NEB c.19102-6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.027 in 233910 control chromosomes, predominantly at a frequency of 0.036 within the Non-Finnish European subpopulation in the gnomAD database, including 68 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.19102-6C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nemaline myopathy 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs145127681; hg19: chr2-152417628;