rs1553875590

Positions:

• chr2-151606691-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164508.2(NEB):​c.12662A>G​(p.Asn4221Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 14)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.02

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22864175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12662A>G	p.Asn4221Ser	missense_variant	84/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12662A>G	p.Asn4221Ser	missense_variant	84/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12662A>G	p.Asn4221Ser	missense_variant	84/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.12662A>G	p.Asn4221Ser	missense_variant	84/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+3118A>G		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 11, 2016	This sequence change replaces asparagine with serine at codon 4421 of the NEB protein (p.Asn4421Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. 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 population databases (ExAC no frequency) and has not been reported in the literature in individuals with a 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 (Align-GVGD: C0, SIFT: Tolerated) suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.010	.;T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D;D;.;.
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.36	N;.;N;.;.
REVEL	Benign	0.089
Sift	Uncertain	0.016	D;.;D;.;.
Sift4G	Benign	0.095	T;T;T;T;T
Vest4		0.091
MutPred		0.42		Loss of ubiquitination at K4218 (P = 0.0818);Loss of ubiquitination at K4218 (P = 0.0818);Loss of ubiquitination at K4218 (P = 0.0818);Loss of ubiquitination at K4218 (P = 0.0818);Loss of ubiquitination at K4218 (P = 0.0818);
MVP		0.67
MPC		0.25
ClinPred		0.47	T
GERP RS		4.0
gMVP		0.00093

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: rs1553875590; hg19: chr2-152463205;