rs1553871396

Positions:

• chr2-151604567-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001164508.2(NEB):​c.13052A>G​(p.Gln4351Arg) variant causes a missense change. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 4)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13052A>G	p.Gln4351Arg	missense_variant	85/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13052A>G	p.Gln4351Arg	missense_variant	85/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13052A>G	p.Gln4351Arg	missense_variant	85/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.13052A>G	p.Gln4351Arg	missense_variant	85/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+5242A>G		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 22, 2016

This sequence change replaces glutamine with arginine at codon 4351 of the NEB protein (p.Gln4351Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change. In summary, this variant is a novel missense change that is not predicted to affect 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.62
DEOGEN2	Benign	0.034	.;T;.;.;.
Eigen	Benign	0.034
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;D;T;.;.
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Benign	-0.68	T
PROVEAN	Benign	-0.73	N;.;N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.47
MutPred		0.72		Loss of ubiquitination at K4346 (P = 0.052);Loss of ubiquitination at K4346 (P = 0.052);Loss of ubiquitination at K4346 (P = 0.052);Loss of ubiquitination at K4346 (P = 0.052);Loss of ubiquitination at K4346 (P = 0.052);
MVP		0.68
MPC		0.16
ClinPred		0.35	T
GERP RS		3.2
gMVP		0.0077

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: rs1553871396; hg19: chr2-152461081;