rs199791504

Positions:

• chr2-151546002-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164508.2(NEB):​c.20467-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (7 hom., cov: 0)
  • Exomes 𝑓: 0.013 (19 hom.)
• Consequence: NEB NM_001164508.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001815
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.613

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]

LOC124906081 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-151546002-A-T is Benign according to our data. Variant chr2-151546002-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 95111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151546002-A-T is described in Lovd as [Benign]. Variant chr2-151546002-A-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.20467-4T>A		splice_region_variant, intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20467-4T>A		splice_region_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.20467-4T>A		splice_region_variant, intron_variant		5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20467-4T>A		splice_region_variant, intron_variant		5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes AF: 0.0424 AC: 1237 AN: 29190 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0431

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.109

Gnomad NFE AF: 0.0843

Gnomad OTH AF: 0.0585

GnomAD3 exomes AF: 0.0957 AC: 2496 AN: 26088 Hom.: 662 AF XY: 0.0966 AC XY: 1355 AN XY: 14032

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.0632

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.0404

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.0128 AC: 8846 AN: 693182 Hom.: 19 Cov.: 17 AF XY: 0.0131 AC XY: 4541 AN XY: 345514

Gnomad4 AFR exome AF: 0.00440

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.000401

Gnomad4 SAS exome AF: 0.00699

Gnomad4 FIN exome AF: 0.00605

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0424 AC: 1238 AN: 29192 Hom.: 7 Cov.: 0 AF XY: 0.0423 AC XY: 593 AN XY: 14016

Gnomad4 AFR AF: 0.00847

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0431

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0287

Gnomad4 NFE AF: 0.0844

Gnomad4 OTH AF: 0.0570

Alfa AF: 0.00961 Hom.: 3

Bravo AF: 0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely 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)	-	- -

Nemaline myopathy 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.074
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0040
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: rs199791504; hg19: chr2-152402516;