rs786204430

Positions:

• chr2-151684828-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001164507.2(NEB):​c.2784del​(p.Asp929IlefsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEB NM_001164507.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -3.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 2-151684828-CA-C is Pathogenic according to our data. Variant chr2-151684828-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151684828-CA-C is described in Lovd as [Pathogenic]. Variant chr2-151684828-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.2784del	p.Asp929IlefsTer28	frameshift_variant	28/182	ENST00000427231.7
NEB	NM_001164508.2	c.2784del	p.Asp929IlefsTer28	frameshift_variant	28/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.2784del	p.Asp929IlefsTer28	frameshift_variant	28/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.2784del	p.Asp929IlefsTer28	frameshift_variant	28/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.2784del	p.Asp929IlefsTer28	frameshift_variant	28/150	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247870 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 05, 2023	This sequence change creates a premature translational stop signal (p.Asp929Ilefs*28) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs786204430, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 26197980). ClinVar contains an entry for this variant (Variation ID: 188731). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Nemaline myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 23, 2017

Variant summary: The NEB c.2784delT (p.Asp929Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent NEB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (e.g. c.11164C>T (p.Arg3722X), c.24218C>A (p.Ser8073X), and c.24559C>T (p.Arg8187X)). This variant is absent in 112170 control chromosomes. A publication cites the variant in an affected individual indicated to have severe NM, who was a compound heterozygote for the variant (paternally inherited) and a four-copy gain (maternally inherited). In addition, a clinical diagnostic laboratory classified the variant as "likely pathogenic", without evidence to independently evaluation. Taken together, the variant of interest has been classified as "pathogenic." -

Arthrogryposis multiplex congenita 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 06, 2023

- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204430; hg19: chr2-152541342;