rs549794342

Variant names:

• chr2-151501423-G-A
• rs549794342
• NM_001164507.2:c.23989C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-151501423-G-A
• chr2-151501423-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001164508.2(NEB):​c.23989C>T​(p.Arg7997*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,548,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: NEB NM_001164508.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 U:2
• Conservation: PhyloP100: 0.865
• 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

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-151501423-G-A is Pathogenic according to our data. Variant chr2-151501423-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373977.

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.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.24094C>T	p.Arg8032*	stop_gained	Exon 169 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.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23989C>T	p.Arg7997*	stop_gained	Exon 168 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000688578.1		c.772C>T	p.Arg258*	stop_gained	Exon 9 of 21	ENSP00000509628.1	A0A8I5KS37

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000272 AC: 43 AN: 157874 AF XY: 0.000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.000310 AC: 433 AN: 1396230 Hom.: 0 Cov.: 29 AF XY: 0.000335 AC XY: 231 AN XY: 688560

African (AFR) AF: 0.0000951 AC: 3 AN: 31546

American (AMR) AF: 0.0000841 AC: 3 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 25088

East Asian (EAS) AF: 0.00 AC: 0 AN: 35796

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78496

European-Finnish (FIN) AF: 0.000793 AC: 39 AN: 49174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000339 AC: 365 AN: 1076946

Other (OTH) AF: 0.000329 AC: 19 AN: 57838

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74394

African (AFR) AF: 0.0000723 AC: 3 AN: 41514

American (AMR) AF: 0.000196 AC: 3 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.000218 AC: 19

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	1	-	Nemaline myopathy 2 (8)
8	-	-	not provided (8)
1	1	-	Nemaline myopathy (2)
2	-	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (2)
1	-	-	Arthrogryposis multiplex congenita 6 (1)
1	-	-	Muscular dystrophy;C0030196:Limb pain;C1836156:Progressive proximal muscle weakness (1)
1	-	-	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	46
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		0.86
Vest4		0.76
ClinPred		0.35	T
GERP RS		-2.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: -32

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

Other links and lift over

dbSNP: rs549794342; hg19: chr2-152357937;