chr2-151493381-GCT-G

Variant names:

• chr2-151493381-GCT-G
• rs776059611
• NM_001164507.2:c.24735_24736delAG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001164508.2(NEB):​c.24735_24736delAG​(p.Arg8245SerfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000496 in 1,611,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NEB NM_001164508.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.64
• Publications: 3 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-151493381-GCT-G is Pathogenic according to our data. Variant chr2-151493381-GCT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 552874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.24735_24736delAG	p.Arg8245SerfsTer2	frameshift	Exon 176 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.24735_24736delAG	p.Arg8245SerfsTer2	frameshift	Exon 176 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24840_24841delAG	p.Arg8280SerfsTer2	frameshift	Exon 177 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.24735_24736delAG	p.Arg8245SerfsTer2	frameshift	Exon 176 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.24735_24736delAG	p.Arg8245SerfsTer2	frameshift	Exon 176 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.481-1842_481-1841delTC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247816 AF XY: 0.00000744

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459470 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725934

African (AFR) AF: 0.000120 AC: 4 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110844

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74276

African (AFR) AF: 0.0000966 AC: 4 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Nemaline myopathy 2 (4)
2	-	-	Nemaline myopathy (2)
2	-	-	not provided (2)
1	-	-	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs776059611; hg19: chr2-152349895;