rs1006363

Positions:

• chr10-20819448-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006393.3(NEBL):​c.2031G>A​(p.Arg677=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,702 control chromosomes in the GnomAD database, including 66,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4653 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61714 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0920

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-20819448-C-T is Benign according to our data. Variant chr10-20819448-C-T is described in ClinVar as [Benign]. Clinvar id is 45489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.2031G>A	p.Arg677=	synonymous_variant	20/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.2031G>A	p.Arg677=	synonymous_variant	20/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33874 AN: 151958 Hom.: 4653 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.247 AC: 62107 AN: 251314 Hom.: 8586 AF XY: 0.250 AC XY: 33907 AN XY: 135824

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.228

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.284 AC: 414474 AN: 1461626 Hom.: 61714 Cov.: 37 AF XY: 0.281 AC XY: 204568 AN XY: 727142

Gnomad4 AFR exome AF: 0.0522

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.223 AC: 33870 AN: 152076 Hom.: 4653 Cov.: 32 AF XY: 0.226 AC XY: 16784 AN XY: 74348

Gnomad4 AFR AF: 0.0641

Gnomad4 AMR AF: 0.205

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.226

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.191

Alfa AF: 0.266 Hom.: 6848

Bravo AF: 0.201

Asia WGS AF: 0.182 AC: 635 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.271

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Arg677Arg in Exon 20 of NEBL: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence and has been identified in 29.6% (2079/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1006363). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1006363; hg19: chr10-21108377; COSMIC: COSV65801322; COSMIC: COSV65801322;