rs1321911647

Positions:

• chr2-151658039-T-C

Variant summary

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

The NM_001164507.2(NEB):​c.6127A>G​(p.Arg2043Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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	Protein	UniProt
NEB	NM_001164507.2	c.6127A>G	p.Arg2043Gly	missense_variant	48/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.6127A>G	p.Arg2043Gly	missense_variant	48/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.6127A>G	p.Arg2043Gly	missense_variant	48/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.6127A>G	p.Arg2043Gly	missense_variant	48/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.6127A>G	p.Arg2043Gly	missense_variant	48/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458978 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725620

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;.;T;.;D;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.2	D;D;.;D;D;.;.
REVEL	Benign	0.19
Sift	Benign	0.088	T;D;.;D;T;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.
Vest4		0.79
MutPred		0.40		Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);Loss of methylation at R2043 (P = 0.0349);
MVP		0.32
MPC		0.36
ClinPred		0.93	D
GERP RS		0.59
Varity_R		0.17
gMVP		0.34

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: rs1321911647; hg19: chr2-152514553;