rs1553984101

Positions:

• chr2-151644128-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001164507.2(NEB):​c.7646A>G​(p.Tyr2549Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.006208
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.7646A>G	p.Tyr2549Cys	missense_variant, splice_region_variant	57/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.7646A>G	p.Tyr2549Cys	missense_variant, splice_region_variant	57/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.7646A>G	p.Tyr2549Cys	missense_variant, splice_region_variant	57/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.7646A>G	p.Tyr2549Cys	missense_variant, splice_region_variant	57/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.7646A>G	p.Tyr2549Cys	missense_variant, splice_region_variant	57/150	5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 09, 2022

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. 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"). ClinVar contains an entry for this variant (Variation ID: 465636). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2549 of the NEB protein (p.Tyr2549Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;.;T;.;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;D;D;D;T;.;.
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.7	D;D;.;D;D;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	D;T;.;T;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.73
MutPred		0.53		Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);Gain of methylation at K2550 (P = 0.017);
MVP		0.68
MPC		0.37
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0062
dbscSNV1_RF	Benign	0.030
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: rs1553984101; hg19: chr2-152500642;