rs1057521174

Variant names:

• chr2-151602007-T-G
• rs1057521174
• NM_001164507.2:c.13370A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001164507.2(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. 15/20 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_001164507.2 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
• Publications: 0 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 381802.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	Exon 88 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.13370A>C	p.Lys4457Thr	missense_variant, splice_region_variant	Exon 88 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000409198.5	c.11601+7802A>C		intron_variant	Intron 78 of 149	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

Dec 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Dec 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		1.1
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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1057521174; hg19: chr2-152458521;