rs41277370

chr10-20845353-C-Gchr10-20845353-C-T

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.1132G>C(p.Asp378His) variant causes a missense change. The variant allele was found at a frequency of 0.0731 in 1,588,688 control chromosomes in the GnomAD database, including 4,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (365 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4564 hom.)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.21

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 (MetaRNN=0.002236694).
• BP6: Variant 10-20845353-C-G is Benign according to our data. Variant chr10-20845353-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 45475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.1132G>C	p.Asp378His	missense_variant	12/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.1132G>C	p.Asp378His	missense_variant	12/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8887 AN: 152030 Hom.: 365 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.0432

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0808

Gnomad OTH AF: 0.0841

GnomAD3 exomes AF: 0.0664 AC: 16617 AN: 250238 Hom.: 684 AF XY: 0.0698 AC XY: 9448 AN XY: 135282

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.0190

Gnomad SAS exome AF: 0.0719

Gnomad FIN exome AF: 0.0462

Gnomad NFE exome AF: 0.0813

Gnomad OTH exome AF: 0.0804

GnomAD4 exome AF: 0.0747 AC: 107242 AN: 1436538 Hom.: 4564 Cov.: 28 AF XY: 0.0753 AC XY: 53922 AN XY: 716038

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.0438

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.0719

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.0782

Gnomad4 OTH exome AF: 0.0825

GnomAD4 genome AF: 0.0584 AC: 8887 AN: 152150 Hom.: 365 Cov.: 32 AF XY: 0.0569 AC XY: 4230 AN XY: 74404

Gnomad4 AFR AF: 0.0189

Gnomad4 AMR AF: 0.0538

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.0228

Gnomad4 SAS AF: 0.0660

Gnomad4 FIN AF: 0.0432

Gnomad4 NFE AF: 0.0808

Gnomad4 OTH AF: 0.0833

Alfa AF: 0.0723 Hom.: 174

Bravo AF: 0.0586

TwinsUK AF: 0.0717 AC: 266

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.0828 AC: 712

ExAC AF: 0.0648 AC: 7866

Asia WGS AF: 0.0470 AC: 164 AN: 3476

EpiCase AF: 0.0894

EpiControl AF: 0.0950

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely 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	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Asp378His in Exon 12 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 8.2% (578/7018) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41277370). -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2012

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

NEBL-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.91	P
Vest4		0.21
MPC		0.10
ClinPred		0.027	T
GERP RS		4.2
Varity_R		0.51
gMVP		0.41

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: rs41277370; hg19: chr10-21134282; COSMIC: COSV65801966; COSMIC: COSV65801966;