2-151664532-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164507.2(NEB):c.5420C>G(p.Ala1807Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A1807V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.5420C>G	p.Ala1807Gly	missense_variant	44/182	ENST00000427231.7
NEB	NM_001164508.2	c.5420C>G	p.Ala1807Gly	missense_variant	44/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.5420C>G	p.Ala1807Gly	missense_variant	44/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.5420C>G	p.Ala1807Gly	missense_variant	44/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.5420C>G	p.Ala1807Gly	missense_variant	44/150	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Invitae

Nov 02, 2021

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"). This missense change has been observed in individual(s) with clinical features of nemaline myopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1807 of the NEB protein (p.Ala1807Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;.
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.6	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.7	N;N;.;N;N;.;.
REVEL	Benign	0.28
Sift	Benign	0.18	T;T;.;T;T;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.52
MutPred		0.56		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.60
MPC		0.33
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.32
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-152521046;