rs367881797

Positions:

• chr2-151581472-T-C

Variant summary

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

The NM_001164507.2(NEB):​c.16284+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (65 hom., cov: 11)
  • Exomes 𝑓: 0.032 (434 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.494

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=-0.94).
• BP6: Variant 2-151581472-T-C is Benign according to our data. Variant chr2-151581472-T-C is described in ClinVar as [Benign]. Clinvar id is 257759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151581472-T-C is described in Lovd as [Benign]. Variant chr2-151581472-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.16284+11A>G		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.16284+11A>G		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.16284+11A>G		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.16284+11A>G		intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11602-5118A>G		intron_variant		5		ENSP00000386259
NEB	ENST00000413693.5	c.474+11A>G		intron_variant		5		ENSP00000410961

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 3175 AN: 94810 Hom.: 65 Cov.: 11

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.0331

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0318

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0546

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0280 AC: 3050 AN: 109098 Hom.: 63 AF XY: 0.0281 AC XY: 1628 AN XY: 57890

Gnomad AFR exome AF: 0.0522

Gnomad AMR exome AF: 0.0199

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0306

Gnomad FIN exome AF: 0.0232

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0321 AC: 20742 AN: 646124 Hom.: 434 Cov.: 9 AF XY: 0.0322 AC XY: 10840 AN XY: 336482

Gnomad4 AFR exome AF: 0.0559

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.00248

Gnomad4 SAS exome AF: 0.0312

Gnomad4 FIN exome AF: 0.0263

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0335 AC: 3183 AN: 94920 Hom.: 65 Cov.: 11 AF XY: 0.0331 AC XY: 1453 AN XY: 43856

Gnomad4 AFR AF: 0.0485

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0318

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.0328

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0334

Alfa AF: 0.0384 Hom.: 39

Bravo AF: 0.0387

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	-0.94
CADD	Benign	0.037
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs367881797; hg19: chr2-152437986;