NM_006393.3:c.259-8dupT

Variant names:

• chr10-20888214-G-GA
• rs57918610
• NM_006393.3:c.259-8dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006393.3(NEBL):​c.259-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,389,664 control chromosomes in the GnomAD database, including 1,471 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (928 hom., cov: 31)
  • Exomes 𝑓: 0.012 (543 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.367
• Publications: 0 publications found

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]

NEBL Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 10-20888214-G-GA is Benign according to our data. Variant chr10-20888214-G-GA is described in ClinVar as Benign. ClinVar VariationId is 45495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.259-8dupT		splice_region intron	N/A	NP_006384.1
	NEBL	NM_001377322.1		c.357+73457dupT		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.357+73457dupT		intron	N/A	NP_998734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.259-8_259-7insT		splice_region intron	N/A	ENSP00000366326.4
	NEBL	ENST00000417816.2	TSL:1	c.357+73457_357+73458insT		intron	N/A	ENSP00000393896.2
	NEBL	ENST00000377119.5	TSL:5	n.269-8_269-7insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 9660 AN: 113292 Hom.: 925 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0100

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0564

Gnomad NFE AF: 0.00468

Gnomad OTH AF: 0.0605

GnomAD2 exomes AF: 0.0222 AC: 4734 AN: 213600 AF XY: 0.0179

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0284

Gnomad FIN exome AF: 0.0000973

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0122 AC: 15621 AN: 1276262 Hom.: 543 Cov.: 23 AF XY: 0.0114 AC XY: 7283 AN XY: 639522

African (AFR) AF: 0.211 AC: 6082 AN: 28846

American (AMR) AF: 0.0181 AC: 736 AN: 40608

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 302 AN: 23676

East Asian (EAS) AF: 0.0309 AC: 1136 AN: 36714

South Asian (SAS) AF: 0.00689 AC: 533 AN: 77334

European-Finnish (FIN) AF: 0.000601 AC: 30 AN: 49912

Middle Eastern (MID) AF: 0.0255 AC: 133 AN: 5210

European-Non Finnish (NFE) AF: 0.00571 AC: 5492 AN: 961000

Other (OTH) AF: 0.0222 AC: 1177 AN: 52962

GnomAD4 genome AF: 0.0854 AC: 9685 AN: 113402 Hom.: 928 Cov.: 31 AF XY: 0.0847 AC XY: 4628 AN XY: 54608

African (AFR) AF: 0.257 AC: 8801 AN: 34206

American (AMR) AF: 0.0351 AC: 361 AN: 10286

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 29 AN: 2900

East Asian (EAS) AF: 0.0289 AC: 130 AN: 4502

South Asian (SAS) AF: 0.00679 AC: 23 AN: 3386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5638

Middle Eastern (MID) AF: 0.0520 AC: 13 AN: 250

European-Non Finnish (NFE) AF: 0.00468 AC: 234 AN: 50028

Other (OTH) AF: 0.0606 AC: 94 AN: 1550

Alfa AF: 0.00775 Hom.: 11

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 26, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 14, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.259-8dup in intron 3 of NEBL: This variant is classified as benign because it has been identified in 23% (4831/20832) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753190853). ACMG/AMP Criteria: BA1.

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEBL-related disorder Benign:1

May 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs57918610; hg19: chr10-21177143;