rs752582527

Variant names:

• chr2-151496969-ACTCT-A
• rs752582527
• NM_001164507.2:c.24361_24364delAGAG

Your query was ambiguous. Multiple possible variants found:

• chr2-151496969-ACTCT-A
• chr2-151496969-ACTCT-ACT
• chr2-151496969-ACTCT-ACTCTCTCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164507.2(NEB):​c.24361_24364delAGAG​(p.Arg8121SerfsTer23) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000007 in 1,427,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R8121R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.66
• Publications: 0 publications found

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: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

Our verdict: Pathogenic. The variant received 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 2-151496969-ACTCT-A is Pathogenic according to our data. Variant chr2-151496969-ACTCT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3584403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.24361_24364delAGAG	p.Arg8121SerfsTer23	frameshift	Exon 172 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.24361_24364delAGAG	p.Arg8121SerfsTer23	frameshift	Exon 172 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.24466_24469delAGAG	p.Arg8156SerfsTer23	frameshift	Exon 173 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.24361_24364delAGAG	p.Arg8121SerfsTer23	frameshift	Exon 172 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24361_24364delAGAG	p.Arg8121SerfsTer23	frameshift	Exon 172 of 182	ENSP00000416578.2
	RIF1	ENST00000457745.1	TSL:1	n.579-813_579-810delTCTC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1427982 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 707000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32924

American (AMR) AF: 0.00 AC: 0 AN: 39676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 38732

South Asian (SAS) AF: 0.00 AC: 0 AN: 81810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092776

Other (OTH) AF: 0.00 AC: 0 AN: 59148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Nemaline myopathy 2 (1)
1	-	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs752582527; hg19: chr2-152353483;