rs112104812

chr10-20888214-G-GAchr10-20888214-G-GAAchr10-20888214-GA-Gchr10-20888214-GAAA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006393.3(NEBL):c.259-8_259-7insT variant causes a splice region, splice polypyrimidine tract, 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. 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.367

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.259-8_259-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.259-8_259-7insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006393.3

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

GnomAD3 exomes AF: 0.0222 AC: 4734 AN: 213600 Hom.: 265 AF XY: 0.0179 AC XY: 2069 AN XY: 115848

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 SAS exome AF: 0.00711

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

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.00689

Gnomad4 FIN exome AF: 0.000601

Gnomad4 NFE exome AF: 0.00571

Gnomad4 OTH exome AF: 0.0222

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

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0100

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.00679

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00468

Gnomad4 OTH AF: 0.0606

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 14, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

NEBL-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2019

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). -

Computational scores

Source: dbNSFP v4.3

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: rs57918610; hg19: chr10-21177143;