rs111841612

chr2-151630818-C-Achr2-151630818-C-T

Variant summary

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

The NM_001164507.2(NEB):c.9620G>T(p.Arg3207Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3207C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.009160
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0740

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.9620G>T	p.Arg3207Leu	missense_variant, splice_region_variant	67/182	ENST00000427231.7
NEB	NM_001164508.2	c.9620G>T	p.Arg3207Leu	missense_variant, splice_region_variant	67/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.9620G>T	p.Arg3207Leu	missense_variant, splice_region_variant	67/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.9620G>T	p.Arg3207Leu	missense_variant, splice_region_variant	67/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.8891G>T	p.Arg2964Leu	missense_variant, splice_region_variant	64/150	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1435168 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 712272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 665888). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 3207 of the NEB protein (p.Arg3207Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.7	M;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D;.;.
REVEL	Benign	0.26
Sift	Benign	0.20	T;T;.;T;T;.;.
Sift4G	Uncertain	0.015	D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;.
Vest4		0.50
MutPred		0.64		Loss of MoRF binding (P = 0.0108);.;.;.;Loss of MoRF binding (P = 0.0108);.;.;
MVP		0.49
MPC		0.30
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.31
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0092
dbscSNV1_RF	Benign	0.064
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: rs111841612; hg19: chr2-152487332;