rs539139958

Positions:

chr2-151617468-G-A

Variant summary

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

The NM_001164508.2(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. R3693L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000095 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

NEB
NM_001164508.2 missense, splice_region

Scores

Splicing: ADA: 0.9865

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.89

Variant links:

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]

NEB links:

NEB (HGNC:):

NEB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2 linkuse as main transcript	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEB	ENST00000397345.8 linkuse as main transcript	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	5	NM_001164508.2	ENSP00000380505.3	P20929-2
NEB	ENST00000427231.7 linkuse as main transcript	c.11077C>T	p.Arg3693Cys	missense_variant, splice_region_variant	75/182	5	NM_001164507.2	ENSP00000416578.2	P20929-3
NEB	ENST00000409198.5 linkuse as main transcript	c.10348C>T	p.Arg3450Cys	missense_variant, splice_region_variant	72/150	5		ENSP00000386259.1	P20929-4
NEB	ENST00000486320.1 linkuse as main transcript	n.18C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000948

AC:

AN:

137144

Hom.:

Cov.:

show subpopulations

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:

AN:

67566

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

35002

show subpopulations

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.:

Cov.:

AF XY:

0.000224

AC XY:

135

AN XY:

601962

show subpopulations

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:

AN:

137194

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

65770

show subpopulations

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.:

ExAC

AF:

0.0000575

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 23, 2022	- -

Nemaline myopathy 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;.;T;.;D;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.96

D;D;D;D;D;.;.

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.21

T;T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.4

M;.;.;.;M;.;.

PrimateAI

Benign

0.31

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over