rs763364977

Positions:

• chr2-151496308-G-A
• chr2-151496308-G-C
• chr2-151496308-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164508.2(NEB):​c.24454C>T​(p.Arg8152*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NEB NM_001164508.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.36

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:):

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-151496308-G-A is Pathogenic according to our data. Variant chr2-151496308-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151496308-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.24454C>T	p.Arg8152*	stop_gained	173/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.24454C>T	p.Arg8152*	stop_gained	173/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.24454C>T	p.Arg8152*	stop_gained	173/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.24454C>T	p.Arg8152*	stop_gained	173/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459414 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 16, 2018	The NEB c.18886C>T (p.Arg6296Ter) variant, also reported as c.24559C>T (p.Arg8187Ter), is a stop-gained variant predicted to result in a premature termination of the protein. The p.Arg8187Ter variant is reported in two studies, in which it is found in two patients in a compound heterozygous state with nemaline myopahty (Lehtokari et al. 2014; Piga et al. 2016). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage, thus the variant is presumed to be rare. Based on the evidence and potential impact of stop-gained variants, the p.Arg6296Ter variant is classified as likely pathogenic for autosomal recessive nemaline myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change creates a premature translational stop signal (p.Arg8187*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 25205138, 27105866). ClinVar contains an entry for this variant (Variation ID: 496135). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 18, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -

Nemaline myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 28, 2016

Variant summary: The NEB c.24559C>T (p.Arg8187X) variant causes a nonsense mutation involving a conserved nucleotide resulting in a truncated NEB protein, a known mechanism for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals in the compound heterozygous state. Publications have indicated that the variant of interest could cause a intermediate phenotype. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 15, 2024

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
Vest4		0.97
ClinPred		0.99	D
GERP RS		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: -32

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

Publications

LitVar

Other links and lift over

dbSNP: rs763364977; hg19: chr2-152352822;