rs10491056

chr10-20831187-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006393.3(NEBL):c.1671+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,590,794 control chromosomes in the GnomAD database, including 112,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14810 hom., cov: 31)
  • Exomes 𝑓: 0.36 (97251 hom.)
• Consequence: NEBL NM_006393.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.250

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-20831187-A-G is Benign according to our data. Variant chr10-20831187-A-G is described in ClinVar as [Benign]. Clinvar id is 45484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.1671+9T>C		intron_variant		ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.1671+9T>C		intron_variant		1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64458 AN: 151818 Hom.: 14779 Cov.: 31

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.455

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.430

GnomAD3 exomes AF: 0.386 AC: 96307 AN: 249204 Hom.: 19836 AF XY: 0.387 AC XY: 52135 AN XY: 134724

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.562

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.362 AC: 520706 AN: 1438858 Hom.: 97251 Cov.: 28 AF XY: 0.363 AC XY: 260488 AN XY: 717304

Gnomad4 AFR exome AF: 0.620

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.417

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.430

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.425 AC: 64543 AN: 151936 Hom.: 14810 Cov.: 31 AF XY: 0.420 AC XY: 31221 AN XY: 74266

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.428

Alfa AF: 0.371 Hom.: 23581

Bravo AF: 0.441

Asia WGS AF: 0.467 AC: 1623 AN: 3478

EpiCase AF: 0.374

EpiControl AF: 0.378

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 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	c.1671+9T>C in Intron 16 of NEBL: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 40.3% (1504/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS; dbSNP rs10491056). -

NEBL-related disorder 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). -

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	-0.79
Cadd	Benign	5.3
Dann	Benign	0.58

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: rs10491056; hg19: chr10-21120116; COSMIC: COSV65801496; COSMIC: COSV65801496;