rs1553875409

Positions:

• chr2-151606667-T-C

Variant summary

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

The NM_001164507.2(NEB):​c.12686A>G​(p.Asp4229Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 14)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.36

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.12686A>G	p.Asp4229Gly	missense_variant	84/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.12686A>G	p.Asp4229Gly	missense_variant	84/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.12686A>G	p.Asp4229Gly	missense_variant	84/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.12686A>G	p.Asp4229Gly	missense_variant	84/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+3142A>G		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.039	.;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;.;.
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.97	D;D;D;D
PROVEAN	Benign	-1.6	N;.;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.15	T;.;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Vest4		0.59
MutPred		0.35		Gain of MoRF binding (P = 0.0443);Gain of MoRF binding (P = 0.0443);Gain of MoRF binding (P = 0.0443);Gain of MoRF binding (P = 0.0443);Gain of MoRF binding (P = 0.0443);
MVP		0.61
MPC		0.35
ClinPred		0.60	D
GERP RS		4.0
gMVP		0.0017

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: rs1553875409; hg19: chr2-152463181;