rs201553266

Variant names:

• chr2-151551738-C-T
• rs201553266
• NM_001164507.2:c.19944G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1 PP4 PP3 PS3 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001164508.2(NEB):c.19944G>A (p.Ser6648=) variant in NEB is a synonymous variant located at the intron exon boundary of exon 129. mRNA characterization of homozygous probands displayed that the variant abolishes the normal donor splice site, shifting towards the use of an alternative (cryptic) splice site in intron 129 which causes a partial intronic retention of 120bp that creates a premature stop codon and shorter polypeptide (PS3) (PMID:26841830, PMID:25205138). The computational splicing predictor SpliceAI gives a score of 0.77 for donor loss, predicting splice site disruption (PP3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001659 (1/6026) alleles) in an unspecified ethnic group (no population codes met). This variant has been identified in at least 9 probands in either a homozygous state or with a second likely pathogenic, pathogenic, or rare uncertain variant (PM3_Strong) (PMID 26841830, 36233295, 25205138, 36233295, 37460656, 32222963, 36714460). At least one proband homozygous for the variant had an affected sibling also homozygous for the variant (PP1) (PMID:37460656). Nemaline rods have been observed in at least one proband identified with the variant (PP4) (PMID:26841830). In summary, this variant meets the criteria to be classified as pathogenic for Nemaline Myopathy for autosomal recessive inheritance based on the ACMG/AMP criteria applied as specified by the ClinGen Congenital Myopathy VCEP: (PS3, PM3_Strong, PP4, PP3, PP1); ClinGen Congenital Myopathies VCEP Specifications version 1.0.0; 5/12/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1907493/MONDO:0018958/146

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NEB NM_004543.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:2
• Conservation: PhyloP100: 0.745
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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 11 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004543.5. 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.19944G>A	p.Ser6648Ser	synonymous	Exon 129 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.19944G>A	p.Ser6648Ser	synonymous	Exon 129 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.19944G>A	p.Ser6648Ser	synonymous	Exon 129 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.19944G>A	p.Ser6648Ser	synonymous	Exon 129 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19944G>A	p.Ser6648Ser	synonymous	Exon 129 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.14841G>A	p.Ser4947Ser	splice_region synonymous	Exon 102 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248206 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460308 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726526

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.0000896 AC: 4 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39606

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110884

Other (OTH) AF: 0.0000332 AC: 2 AN: 60314

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	1	-	Nemaline myopathy 2 (5)
3	1	-	not provided (4)
3	-	-	Nemaline myopathy (3)
2	-	-	Arthrogryposis multiplex congenita 6 (2)
2	-	-	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.53
PhyloP100		0.74
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 0

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

Other links and lift over

dbSNP: rs201553266; hg19: chr2-152408252;