rs1192545815

Positions:

• chr2-151601971-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164507.2(NEB):​c.13406C>T​(p.Thr4469Ile) 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.128

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12959322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.13406C>T	p.Thr4469Ile	missense_variant	88/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.13406C>T	p.Thr4469Ile	missense_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.13406C>T	p.Thr4469Ile	missense_variant	88/182	5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.13406C>T	p.Thr4469Ile	missense_variant	88/182	5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.11601+7838C>T		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 FAILED QC

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 0

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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.	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.020	.;T;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.78	T;T;T;.;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.96	D;D;N;N
PROVEAN	Benign	-0.58	N;.;N;.;.
REVEL	Benign	0.033
Sift	Benign	0.15	T;.;T;.;.
Sift4G	Benign	0.13	T;T;T;T;T
Vest4		0.19
MutPred		0.37		Loss of phosphorylation at T4469 (P = 0.0388);Loss of phosphorylation at T4469 (P = 0.0388);Loss of phosphorylation at T4469 (P = 0.0388);Loss of phosphorylation at T4469 (P = 0.0388);Loss of phosphorylation at T4469 (P = 0.0388);
MVP		0.21
MPC		0.32
ClinPred		0.12	T
GERP RS		-1.4
gMVP		0.0032

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: rs1192545815; hg19: chr2-152458485;