2-151650245-G-C

Variant names:

• chr2-151650245-G-C
• rs1057518861
• NM_001164507.2:c.7362C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164508.2(NEB):​c.7362C>G​(p.Asn2454Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.64

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20875031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.7362C>G	p.Asn2454Lys	missense_variant	Exon 54 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.7362C>G	p.Asn2454Lys	missense_variant	Exon 54 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.7362C>G	p.Asn2454Lys	missense_variant	Exon 54 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.7362C>G	p.Asn2454Lys	missense_variant	Exon 54 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.7362C>G	p.Asn2454Lys	missense_variant	Exon 54 of 150	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Muscle weakness;C0699743:Congenital muscular dystrophy Uncertain:1

May 21, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;.;T;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;D;D;D;T;.;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N;N;.;N;N;.;.
REVEL	Benign	0.042
Sift	Benign	0.29	T;T;.;T;T;.;.
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D
Polyphen		0.45	.;.;.;.;B;.;.
Vest4		0.47
MutPred		0.41		Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);Gain of methylation at N2454 (P = 0.014);
MVP		0.37
MPC		0.12
ClinPred		0.46	T
GERP RS		4.3
Varity_R		0.087
gMVP		0.30

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: rs1057518861; hg19: chr2-152506759;