rs1553708977

Variant names:

• chr2-151546001-T-TTA
• rs1553708977
• NM_001164507.2:c.20467-4_20467-3insTA

Your query was ambiguous. Multiple possible variants found:

• chr2-151546001-T-TTA
• chr2-151546001-T-TTAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001164507.2(NEB):​c.20467-4_20467-3insTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.613
• 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

LOC124906081 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-151546001-T-TTA is Benign according to our data. Variant chr2-151546001-T-TTA is described in ClinVar as Likely_benign. ClinVar VariationId is 465539.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.20467-4_20467-3insTA		splice_region_variant, intron_variant	Intron 134 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.20467-4_20467-3insTA		splice_region_variant, intron_variant	Intron 134 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.20467-4_20467-3insTA		splice_region_variant, intron_variant	Intron 134 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.20467-4_20467-3insTA		splice_region_variant, intron_variant	Intron 134 of 181	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000407 AC: 33 AN: 809956 Hom.: 0 Cov.: 17 AF XY: 0.0000167 AC XY: 7 AN XY: 418442

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

African (AFR) AF: 0.0000502 AC: 1 AN: 19936

American (AMR) AF: 0.00 AC: 0 AN: 23334

Ashkenazi Jewish (ASJ) AF: 0.0000505 AC: 1 AN: 19790

East Asian (EAS) AF: 0.0000625 AC: 2 AN: 31986

South Asian (SAS) AF: 0.00 AC: 0 AN: 60890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4298

European-Non Finnish (NFE) AF: 0.0000432 AC: 25 AN: 578324

Other (OTH) AF: 0.000105 AC: 4 AN: 37984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000425215), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Benign:1

Jun 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

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		-0.61
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1553708977; hg19: chr2-152402515;