rs539139958

chr2-151617468-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001164507.2(NEB):c.11077C>T(p.Arg3693Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,362,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to 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. R3693H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: NEB NM_001164507.2 missense, splice_region
• Scores: Splicing: ADA: 0.9865
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	ENST00000427231.7
NEB	NM_001164508.2	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.10348C>T	p.Arg3450Cys	missense_variant, splice_region_variant	72/150	5
NEB	ENST00000486320.1	n.18C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000948 AC: 13 AN: 137144 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000154

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 14 AN: 67566 Hom.: 0 AF XY: 0.000229 AC XY: 8 AN XY: 35002

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000273

Gnomad EAS exome AF: 0.000182

Gnomad SAS exome AF: 0.000127

Gnomad FIN exome AF: 0.000507

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 295 AN: 1225474 Hom.: 0 Cov.: 23 AF XY: 0.000224 AC XY: 135 AN XY: 601962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000145

Gnomad4 EAS exome AF: 0.0000301

Gnomad4 SAS exome AF: 0.0000682

Gnomad4 FIN exome AF: 0.000120

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.0000978

GnomAD4 genome AF: 0.0000948 AC: 13 AN: 137194 Hom.: 0 Cov.: 29 AF XY: 0.000106 AC XY: 7 AN XY: 65770

Gnomad4 AFR AF: 0.0000830

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: 0.000154

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000183 Hom.: 0

ExAC AF: 0.0000575 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Nemaline myopathy 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3693 of the NEB protein (p.Arg3693Cys). This variant is present in population databases (rs539139958, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465434). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;M;.;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D;D;.;D;D;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.052	T;T;.;D;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.
Vest4		0.37
MVP		0.67
MPC		0.37
ClinPred		0.29	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
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: rs539139958; hg19: chr2-152473982;