rs886038439

Positions:

• chr2-151600550-C-G
• chr2-151600550-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001164507.2(NEB):​c.13680G>C​(p.Gln4560His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.62

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 -1 ACMG points.

• BP6: Variant 2-151600550-C-G is Benign according to our data. Variant chr2-151600550-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13680G>C	p.Gln4560His	missense_variant	89/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13680G>C	p.Gln4560His	missense_variant	89/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13680G>C	p.Gln4560His	missense_variant	89/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.13680G>C	p.Gln4560His	missense_variant	89/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+9259G>C		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000263 AC: 2 AN: 7594 Hom.: 0 Cov.: 0 AF XY: 0.000246 AC XY: 1 AN XY: 4072

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: 0.000520

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

This sequence change replaces glutamine with histidine at codon 4560 of the NEB protein (p.Gln4560His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This variant is not present in the population databases and has not been reported in the literature in individuals with NEB-related disease. However, it occurs in the triplicated region of NEB and the frequency data is considered unreliable. Algorithms developed to predict the effect of missense changes on protein structure and function are not able to calculate the potential effect of amino acid changes in this region. In summary, this variant is a novel missense change with an uncertain impact on protein function. Missense variants in the NEB gene are typically not pathogenic, and there is no indication that this variant causes disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.35
DEOGEN2	Benign	0.019	.;T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.56	N;.;N;.;.
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.44
MutPred		0.61		Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);Loss of ubiquitination at K4557 (P = 0.0768);
MVP		0.48
MPC		0.13
ClinPred		0.18	T
GERP RS		2.5
gMVP		0.012

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886038439; hg19: chr2-152457064;