rs56026241

chr2-151531901-AT-Achr2-151531901-AT-ATT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001164507.2(NEB):c.21418-6del 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 0.602 in 1,566,634 control chromosomes in the GnomAD database, including 288,858 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24355 hom., cov: 0)
  • Exomes 𝑓: 0.61 (264503 hom.)
• Consequence: NEB NM_001164507.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.54

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]

RIF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-151531901-AT-A is Benign according to our data. Variant chr2-151531901-AT-A is described in ClinVar as [Benign]. Clinvar id is 95112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151531901-AT-A is described in Lovd as [Benign]. Variant chr2-151531901-AT-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21418-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000427231.7
NEB	NM_001164508.2	c.21418-6del		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.21418-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21418-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84079 AN: 151834 Hom.: 24334 Cov.: 0

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.591 AC: 127200 AN: 215382 Hom.: 38523 AF XY: 0.581 AC XY: 67119 AN XY: 115620

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.583

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.610

GnomAD4 exome AF: 0.607 AC: 858614 AN: 1414682 Hom.: 264503 Cov.: 0 AF XY: 0.601 AC XY: 422334 AN XY: 702968

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.713

Gnomad4 ASJ exome AF: 0.520

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.590

GnomAD4 genome AF: 0.554 AC: 84129 AN: 151952 Hom.: 24355 Cov.: 0 AF XY: 0.556 AC XY: 41269 AN XY: 74260

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.681

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.558

Alfa AF: 0.593 Hom.: 4866

Bravo AF: 0.554

Asia WGS AF: 0.450 AC: 1568 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 27, 2017	Variant summary: c.21523-6dupA in NEB gene is an intronic change that involves a mildly conserved nucleotide. 3/5 programs in Alamut predict that this variant does not have significant effect on the normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.6045 (49666 /82164chrs tested), including numerous homozygotes across multiple populations. The observed frequency exceed the maximum expected allele frequency for a pathogenic variant of 0.0035. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign by reputable databases/clinical laboratories. Considering all, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2019	- -

Nemaline myopathy 2 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Nemaline Myopathy, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56026241; hg19: chr2-152388415;