rs2296610

Positions:

• chr10-20868692-G-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.656C>A​(p.Ala219Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00787 in 1,611,660 control chromosomes in the GnomAD database, including 673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A219T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (577 hom.)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.86

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]

LOC102725112 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026087463).
• BP6: Variant 10-20868692-G-T is Benign according to our data. Variant chr10-20868692-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 45500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20868692-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.656C>A	p.Ala219Asp	missense_variant	7/28	ENST00000377122.9
LOC102725112	XR_007062082.1	n.351+3225G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.656C>A	p.Ala219Asp	missense_variant	7/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1916 AN: 152022 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.0199 AC: 4988 AN: 251144 Hom.: 279 AF XY: 0.0184 AC XY: 2497 AN XY: 135724

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0522

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.00738 AC: 10775 AN: 1459520 Hom.: 577 Cov.: 31 AF XY: 0.00719 AC XY: 5219 AN XY: 726252

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.00383

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0126 AC: 1911 AN: 152140 Hom.: 96 Cov.: 32 AF XY: 0.0166 AC XY: 1237 AN XY: 74380

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.0639

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00561 Hom.: 99

Bravo AF: 0.0105

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0179 AC: 2174

Asia WGS AF: 0.0640 AC: 220 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

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 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Ala219Asp in Exon 07 of NEBL: This variant is not expected to have clinical si gnificance because it has been identified in 20.7% (17/82) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs2 296610). -
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. -

NEBL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2013

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.000034	P;P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.31
MPC		0.13
ClinPred		0.028	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2296610; hg19: chr10-21157621; COSMIC: COSV65800031;