rs1159204491

Positions:

• chr2-151697639-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.1162A>G​(p.Lys388Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K388K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.91

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, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.1162A>G	p.Lys388Glu	missense_variant	14/182	ENST00000427231.7
NEB	NM_001164508.2	c.1162A>G	p.Lys388Glu	missense_variant	14/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.1162A>G	p.Lys388Glu	missense_variant	14/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.1162A>G	p.Lys388Glu	missense_variant	14/182	5	NM_001164507.2	A2
NEB	ENST00000489048.1	n.61A>G		non_coding_transcript_exon_variant	2/12	1
NEB	ENST00000409198.5	c.1162A>G	p.Lys388Glu	missense_variant	14/150	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450264 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721216

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 19, 2022	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 388 of the NEB protein (p.Lys388Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 534009). 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"). 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
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;.;.
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.3	M;M;.;M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N;.;N;N;.;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D;D;.;D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.64
MutPred		0.76		Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);Loss of methylation at K388 (P = 0.0129);
MVP		0.85
MPC		0.39
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.53
gMVP		0.31

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: rs1159204491; hg19: chr2-152554153;