NM_001164507.2:c.19712_19716delCTTATinsGAG

Variant names:

• chr2-151553413-ATAAG-CTC
• rs587780397
• NM_001164507.2:c.19712_19716delCTTATinsGAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001164507.2(NEB):​c.19712_19716delCTTATinsGAG​(p.Ala6571GlyfsTer5) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A6571A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164507.2 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• 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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 2-151553413-ATAAG-CTC is Pathogenic according to our data. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-151553413-ATAAG-CTC is described in CliVar as Pathogenic. Clinvar id is 129704.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.19712_19716delCTTATinsGAG	p.Ala6571GlyfsTer5	frameshift_variant, missense_variant	Exon 127 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.19712_19716delCTTATinsGAG	p.Ala6571GlyfsTer5	frameshift_variant, missense_variant	Exon 127 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.19712_19716delCTTATinsGAG	p.Ala6571GlyfsTer5	frameshift_variant, missense_variant	Exon 127 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.19712_19716delCTTATinsGAG	p.Ala6571GlyfsTer5	frameshift_variant, missense_variant	Exon 127 of 182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:1

Feb 07, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs587780397; hg19: chr2-152409927;