rs2296614

Positions:

• chr10-20785795-T-C

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.2997A>G​(p.Thr999=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,613,892 control chromosomes in the GnomAD database, including 5,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (635 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4674 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.181

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=-0.63).
• BP6: Variant 10-20785795-T-C is Benign according to our data. Variant chr10-20785795-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 45497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.181 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.2997A>G	p.Thr999=	synonymous_variant	28/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.2997A>G	p.Thr999=	synonymous_variant	28/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 13018 AN: 152124 Hom.: 634 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0543

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0800 AC: 20073 AN: 250986 Hom.: 1017 AF XY: 0.0756 AC XY: 10249 AN XY: 135628

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.0581

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0756 AC: 110490 AN: 1461650 Hom.: 4674 Cov.: 31 AF XY: 0.0746 AC XY: 54248 AN XY: 727130

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.0960

Gnomad4 EAS exome AF: 0.00176

Gnomad4 SAS exome AF: 0.0587

Gnomad4 FIN exome AF: 0.0539

Gnomad4 NFE exome AF: 0.0756

Gnomad4 OTH exome AF: 0.0793

GnomAD4 genome AF: 0.0855 AC: 13017 AN: 152242 Hom.: 635 Cov.: 32 AF XY: 0.0845 AC XY: 6286 AN XY: 74428

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0524

Gnomad4 NFE AF: 0.0746

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0847 Hom.: 425

Bravo AF: 0.0923

Asia WGS AF: 0.0330 AC: 116 AN: 3478

EpiCase AF: 0.0761

EpiControl AF: 0.0759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Thr999Thr in Exon 28 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 12.4% (462/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs2296614). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2014	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 10, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.1
DANN	Benign	0.59

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: rs2296614; hg19: chr10-21074724;