rs1057521174

Positions:

• chr2-151602007-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001164508.2(NEB):​c.13370A>C​(p.Lys4457Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 0)
• Consequence: NEB NM_001164508.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003472
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.13

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15015852).
• BP6: Variant 2-151602007-T-G is Benign according to our data. Variant chr2-151602007-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	88/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	88/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	88/182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	88/182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+7802A>C		intron_variant		5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2017	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.53
DEOGEN2	Benign	0.024	.;T;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T;T;T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-0.86	N;.;N;.;.
REVEL	Benign	0.023
Sift	Benign	0.15	T;.;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.17
MutPred		0.51		Gain of catalytic residue at K4457 (P = 0.015);Gain of catalytic residue at K4457 (P = 0.015);Gain of catalytic residue at K4457 (P = 0.015);Gain of catalytic residue at K4457 (P = 0.015);Gain of catalytic residue at K4457 (P = 0.015);
MVP		0.32
MPC		0.32
ClinPred		0.12	T
GERP RS		1.6
gMVP		0.0044

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.0040
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: rs1057521174; hg19: chr2-152458521;