rs114875104

Positions:

• chr10-20817668-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006393.3(NEBL):​c.2080C>T​(p.Arg694Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 0.228

Genes affected

NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017885596).
• BP6: Variant 10-20817668-G-A is Benign according to our data. Variant chr10-20817668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45491.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.2080C>T	p.Arg694Trp	missense_variant	21/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.2080C>T	p.Arg694Trp	missense_variant	21/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251062 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135680

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1461216 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 726984

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74420

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000650

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2021	The c.2080C>T (p.R694W) alteration is located in exon 21 (coding exon 21) of the NEBL gene. This alteration results from a C to T substitution at nucleotide position 2080, causing the arginine (R) at amino acid position 694 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 23, 2013	Variant classified as Uncertain Significance - Favor Benign. The Arg694Trp varia nt in NEBL has not been reported in the literature nor previously identified by our laboratory. This variant has been identified in 0.16% (7/4406) of African Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs114875104). This frequency is too l ow to rule out a role in disease. Arginine (Arg) at position 694 is not conserve d in evolution, suggesting that a change to this position may be tolerated. This variant is less likely disease causing but additional studies are needed to ful ly assess its clinical significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2017	A variant of uncertain significance has been identified in the NEBL gene. The R694W variant has not been published as a pathogenic variant or reported as a benign variant, to our knowledge. The NHLBI Exome Sequencing Project, Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project reports R694W was observed in 0.1-0.2% of individuals of African background, indicating it may be a rare (benign) variant in this population. This substitution occurs at a position that is not conserved across species. Nevertheless, the R694W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NEBL NM_006393.2 exon 25 p.Arg694Trp (c.2080C>T): This variant has not been reported in the literature and is present in 0.1% (38/24960) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-21106597-G-A). This variant is present in ClinVar (Variation ID:45491). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

NEBL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.036
Eigen_PC	Benign	-0.0089
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.067
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.94	P
Vest4		0.28
MVP		0.45
MPC		0.055
ClinPred		0.055	T
GERP RS		4.1
Varity_R		0.14
gMVP		0.17

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: rs114875104; hg19: chr10-21106597; COSMIC: COSV65804030; COSMIC: COSV65804030;