rs1553862206

Positions:

• chr2-151600513-G-A

Variant summary

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

The NM_001164507.2(NEB):​c.13717C>T​(p.His4573Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H4573H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.74

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.13717C>T	p.His4573Tyr	missense_variant	89/182	ENST00000427231.7
NEB	NM_001164508.2	c.13717C>T	p.His4573Tyr	missense_variant	89/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.13717C>T	p.His4573Tyr	missense_variant	89/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.13717C>T	p.His4573Tyr	missense_variant	89/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.11601+9296C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.55
DEOGEN2	Benign	0.019	.;T;.;.;.
Eigen	Benign	0.046
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;.;.
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.64	N;.;N;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.58
MutPred		0.57		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP		0.40
MPC		0.12
ClinPred		0.43	T
GERP RS		2.5
gMVP		0.0032

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553862206; hg19: chr2-152457027;