rs1376744526

chr2-151604850-G-A

Variant summary

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

The NM_001164507.2(NEB):c.12769C>T(p.Arg4257Cys) variant causes a missense change. 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. R4257H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 8)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.82

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.12769C>T	p.Arg4257Cys	missense_variant	85/182	ENST00000427231.7
NEB	NM_001164508.2	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.12769C>T	p.Arg4257Cys	missense_variant	85/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+4959C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000485 AC: 3 AN: 61820 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.0000799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000580

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000294 AC: 13 AN: 441778 Hom.: 0 Cov.: 5 AF XY: 0.0000215 AC XY: 5 AN XY: 232596

Gnomad4 AFR exome AF: 0.0000984

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000455

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000241

Gnomad4 OTH exome AF: 0.0000445

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000485 AC: 3 AN: 61820 Hom.: 0 Cov.: 8 AF XY: 0.0000693 AC XY: 2 AN XY: 28858

Gnomad4 AFR AF: 0.0000799

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000580

Gnomad4 OTH AF: 0.00

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.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Benign	0.73
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;.;.
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-2.0	N;.;N;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.53
MutPred		0.65		Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);Loss of MoRF binding (P = 0.0126);
MVP		0.62
MPC		0.37
ClinPred		0.25	T
GERP RS		2.3
gMVP		0.0029

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: rs1376744526; hg19: chr2-152461364;