chr2-151570277-C-T

Position:

• chr2-151570277-C-T

Variant summary

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

The NM_001164508.2(NEB):​c.17234G>A​(p.Arg5745Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,448 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.16

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=0.21626398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.17234G>A	p.Arg5745Gln	missense_variant	109/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.17234G>A	p.Arg5745Gln	missense_variant	109/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.17234G>A	p.Arg5745Gln	missense_variant	109/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.17234G>A	p.Arg5745Gln	missense_variant	109/182	5	NM_001164507.2	ENSP00000416578.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248434 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134760

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: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461448 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726982

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2021	This sequence change replaces arginine with glutamine at codon 5745 of the NEB protein (p.Arg5745Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs773556106, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.029	.;.;T;.;T;T;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;.;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;.;.;.;L;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N;.;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.060	T;T;.;T;T;T;.;.
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T
Polyphen		0.98	.;.;.;.;D;.;.;.
Vest4		0.38
MutPred		0.44		Loss of MoRF binding (P = 0.0345);.;.;.;Loss of MoRF binding (P = 0.0345);.;.;.;
MVP		0.61
MPC		0.34
ClinPred		0.77	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.42

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: rs773556106; hg19: chr2-152426791;