rs1049044616

Positions:

• chr2-151604819-C-T

Variant summary

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

The NM_001164507.2(NEB):​c.12800G>A​(p.Arg4267His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R4267R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 7)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.49

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	UniProt
NEB	NM_001164507.2	c.12800G>A	p.Arg4267His	missense_variant	85/182	ENST00000427231.7
NEB	NM_001164508.2	c.12800G>A	p.Arg4267His	missense_variant	85/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12800G>A	p.Arg4267His	missense_variant	85/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12800G>A	p.Arg4267His	missense_variant	85/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+4990G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 7

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000102 AC: 5 AN: 488206 Hom.: 0 Cov.: 6 AF XY: 0.0000117 AC XY: 3 AN XY: 255706

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: 0.0000444

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000929

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 7

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 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Benign	0.64
DEOGEN2	Benign	0.027	.;T;.;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;.;.
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.50	T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-1.2	N;.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.041	D;.;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.45
MutPred		0.49		Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);
MVP		0.56
MPC		0.34
ClinPred		0.33	T
GERP RS		3.2
gMVP		0.00077

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: rs1049044616; hg19: chr2-152461333;