rs1363996930

Positions:

• chr2-151604829-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164508.2(NEB):​c.12790A>G​(p.Met4264Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 8)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.25

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.095669955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12790A>G	p.Met4264Val	missense_variant	85/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12790A>G	p.Met4264Val	missense_variant	85/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12790A>G	p.Met4264Val	missense_variant	85/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.12790A>G	p.Met4264Val	missense_variant	85/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+4980A>G		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD3 exomes AF: 0.0000385 AC: 2 AN: 51946 Hom.: 0 AF XY: 0.0000383 AC XY: 1 AN XY: 26094

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000263 AC: 13 AN: 495078 Hom.: 0 Cov.: 6 AF XY: 0.0000386 AC XY: 10 AN XY: 259056

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: 0.00

Gnomad4 FIN exome AF: 0.0000409

Gnomad4 NFE exome AF: 0.0000332

Gnomad4 OTH exome AF: 0.0000400

GnomAD4 genome Cov.: 8

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	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2017	This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This variant has not been reported in the literature in individuals with NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.23
DANN	Benign	0.30
DEOGEN2	Benign	0.0020	.;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.67	T;T;T;.;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.096	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	0.83	N;.;N;.;.
REVEL	Benign	0.017
Sift	Benign	1.0	T;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T
Vest4		0.20
MutPred		0.41		Loss of catalytic residue at M4264 (P = 0.0863);Loss of catalytic residue at M4264 (P = 0.0863);Loss of catalytic residue at M4264 (P = 0.0863);Loss of catalytic residue at M4264 (P = 0.0863);Loss of catalytic residue at M4264 (P = 0.0863);
MVP		0.088
MPC		0.052
ClinPred		0.032	T
GERP RS		0.15
gMVP		0.00044

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: rs1363996930; hg19: chr2-152461343;