rs74482326

Positions:

• chr2-151671063-C-A
• chr2-151671063-C-T

Variant summary

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

The NM_001164507.2(NEB):​c.4466G>T​(p.Gly1489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1489D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.828

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.4466G>T	p.Gly1489Val	missense_variant	38/182	ENST00000427231.7
NEB	NM_001164508.2	c.4466G>T	p.Gly1489Val	missense_variant	38/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.4466G>T	p.Gly1489Val	missense_variant	38/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.4466G>T	p.Gly1489Val	missense_variant	38/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.4466G>T	p.Gly1489Val	missense_variant	38/150	5
NEB	ENST00000484968.1	n.318G>T		non_coding_transcript_exon_variant	1/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461666 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727116

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Apr 27, 2019

- -

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2022

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1489 of the NEB protein (p.Gly1489Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 638412). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	.;.;T;.;T;.;.
Eigen	Benign	-0.098
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T;D;D;D;T;.;.
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.47	N;N;.;N;N;N;N
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;.;.
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;.;T;T;.;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T
Polyphen		0.42	.;.;.;.;B;.;.
Vest4		0.61
MutPred		0.51		Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);Loss of catalytic residue at P1485 (P = 0.0914);
MVP		0.43
MPC		0.24
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.25
gMVP		0.28

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: rs74482326; hg19: chr2-152527577;