rs200251444

Positions:

• chr2-151658078-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001164507.2(NEB):​c.6088C>T​(p.Leu2030Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,596,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.46

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01780811).
• BP6: Variant 2-151658078-G-A is Benign according to our data. Variant chr2-151658078-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465622.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.6088C>T	p.Leu2030Phe	missense_variant	48/182	ENST00000427231.7
NEB	NM_001164508.2	c.6088C>T	p.Leu2030Phe	missense_variant	48/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.6088C>T	p.Leu2030Phe	missense_variant	48/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.6088C>T	p.Leu2030Phe	missense_variant	48/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.6088C>T	p.Leu2030Phe	missense_variant	48/150	5

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 30 AN: 233848 Hom.: 0 AF XY: 0.000103 AC XY: 13 AN XY: 126380

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.000152

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000651 AC: 94 AN: 1443892 Hom.: 0 Cov.: 29 AF XY: 0.0000599 AC XY: 43 AN XY: 718062

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.000160

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: 0.00000364

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74450

Gnomad4 AFR AF: 0.00197

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000665

ESP6500AA AF: 0.00166 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000191 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NEB p.Leu2030Phe variant was not identified in the literature nor was it identified in Cosmic, MutDB or LOVD 3.0. The variant was identified in dbSNP (ID: rs200251444) and in ClinVar with conflicting interpretations of pathogenicity (classified as likely benign by Invitae and uncertain significance by EGL Genetic diagnostics). The variant is associated with Nemaline myopathy 2. The variant was identified in control databases in 45 of 265236 chromosomes at a frequency of 0.00017 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 40 of 23168 chromosomes (freq: 0.001727), Latino in 5 of 33694 chromosomes (freq: 0.000148), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Leu2030 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2023	- -

NEB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nemaline myopathy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.83	T;D;D;D;T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.018	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;N;.;N;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.42	T;T;.;T;T;.;.
Sift4G	Benign	0.081	T;T;T;T;T;T;T
Polyphen		0.87	.;.;.;.;P;.;.
Vest4		0.46
MVP		0.54
MPC		0.29
ClinPred		0.053	T
GERP RS		6.0
Varity_R		0.14
gMVP		0.10

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: rs200251444; hg19: chr2-152514592;