NM_001164507.2:c.20263-7dupT

Variant names:

• chr2-151547539-G-GA
• rs763008896
• NM_001164507.2:c.20263-7dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001164507.2(NEB):​c.20263-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,573,452 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: NEB NM_001164507.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.636
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 2-151547539-G-GA is Benign according to our data. Variant chr2-151547539-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465534.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.20263-7dupT		splice_region intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.20263-7dupT		splice_region intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.20263-7dupT		splice_region intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.20263-7_20263-6insT		splice_region intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.20263-7_20263-6insT		splice_region intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.15160-7_15160-6insT		splice_region intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.000173 AC: 26 AN: 150532 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000561

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

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: 0.0000148

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000655 AC: 134 AN: 204518 AF XY: 0.000683

Gnomad AFR exome AF: 0.000896

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.000329

Gnomad EAS exome AF: 0.000690

Gnomad FIN exome AF: 0.000531

Gnomad NFE exome AF: 0.000752

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000526 AC: 749 AN: 1422806 Hom.: 0 Cov.: 30 AF XY: 0.000515 AC XY: 364 AN XY: 706900

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

African (AFR) AF: 0.000642 AC: 21 AN: 32690

American (AMR) AF: 0.000357 AC: 15 AN: 42014

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25358

East Asian (EAS) AF: 0.000311 AC: 12 AN: 38544

South Asian (SAS) AF: 0.000324 AC: 27 AN: 83268

European-Finnish (FIN) AF: 0.000134 AC: 7 AN: 52106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.000591 AC: 641 AN: 1084180

Other (OTH) AF: 0.000373 AC: 22 AN: 58972

⚠️ 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 AF: 0.000186 AC: 28 AN: 150646 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 10 AN XY: 73482

African (AFR) AF: 0.000609 AC: 25 AN: 41084

American (AMR) AF: 0.0000661 AC: 1 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10240

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67564

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Jul 13, 2023

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nemaline myopathy 2 Benign:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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: rs763008896; hg19: chr2-152404053; COSMIC: COSV105847689;