rs200053313

Positions:

• chr2-151590049-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_001164508.2(NEB):​c.15086A>C​(p.Lys5029Thr) 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 Likely benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.82

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19574016).
• BP6: Variant 2-151590049-T-G is Benign according to our data. Variant chr2-151590049-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 257751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.15086A>C	p.Lys5029Thr	missense_variant	97/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.15086A>C	p.Lys5029Thr	missense_variant	97/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.15086A>C	p.Lys5029Thr	missense_variant	97/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.15086A>C	p.Lys5029Thr	missense_variant	97/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11602-13695A>C		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.49
DEOGEN2	Benign	0.037	.;T;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T;T;T;.;.
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;N;N
PROVEAN	Benign	-0.44	N;.;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.033	D;.;D;.;.
Sift4G	Uncertain	0.052	T;T;T;T;T
Vest4		0.16
MutPred		0.51		Loss of methylation at K5029 (P = 0.014);Loss of methylation at K5029 (P = 0.014);Loss of methylation at K5029 (P = 0.014);Loss of methylation at K5029 (P = 0.014);Loss of methylation at K5029 (P = 0.014);
MVP		0.46
MPC		0.32
ClinPred		0.20	T
GERP RS		0.83
gMVP		0.0031

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: rs200053313; hg19: chr2-152446563;