rs11894996

chr2-151552782-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.19732-6C>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 0.0213 in 1,603,208 control chromosomes in the GnomAD database, including 430 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (60 hom., cov: 32)
  • Exomes 𝑓: 0.021 (370 hom.)
• Consequence: NEB NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004533
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.920

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=-0.81).
• BP6: Variant 2-151552782-G-A is Benign according to our data. Variant chr2-151552782-G-A is described in ClinVar as [Benign]. Clinvar id is 129719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151552782-G-A is described in Lovd as [Benign]. Variant chr2-151552782-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0244 (3707/152190) while in subpopulation AFR AF= 0.0386 (1602/41528). AF 95% confidence interval is 0.037. There are 60 homozygotes in gnomad4. There are 1839 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.19732-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.19732-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.19732-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.19732-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3696 AN: 152072 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0193 AC: 4643 AN: 240150 Hom.: 66 AF XY: 0.0185 AC XY: 2404 AN XY: 129856

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00901

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.0000579

Gnomad SAS exome AF: 0.00675

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0210 AC: 30446 AN: 1451018 Hom.: 370 Cov.: 28 AF XY: 0.0203 AC XY: 14648 AN XY: 721736

Gnomad4 AFR exome AF: 0.0400

Gnomad4 AMR exome AF: 0.00987

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00710

Gnomad4 FIN exome AF: 0.0352

Gnomad4 NFE exome AF: 0.0220

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0244 AC: 3707 AN: 152190 Hom.: 60 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74392

Gnomad4 AFR AF: 0.0386

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.0405

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0229 Hom.: 19

Bravo AF: 0.0233

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	-	- -
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	Mar 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2022	- -

Nemaline myopathy 2 Benign:2

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	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.42
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0020
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: rs11894996; hg19: chr2-152409296; COSMIC: COSV50807348;