chr10-20850403-G-T

Position:

chr10-20850403-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006393.3(NEBL):c.1108C>A(p.Gln370Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,596,686 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

NEBL
NM_006393.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 7.62

Variant links:

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 links:

NEBL (HGNC:):

NEBL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011808008).

BP6

Variant 10-20850403-G-T is Benign according to our data. Variant chr10-20850403-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178098.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3 linkuse as main transcript	c.1108C>A	p.Gln370Lys	missense_variant	11/28	ENST00000377122.9	NP_006384.1	O76041-1Q59FZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9 linkuse as main transcript	c.1108C>A	p.Gln370Lys	missense_variant	11/28	1	NM_006393.3	ENSP00000366326.4		O76041-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000892

AC:

224

AN:

251210

Hom.:

AF XY:

0.00120

AC XY:

163

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00693

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000432

AC:

624

AN:

1444452

Hom.:

Cov.:

AF XY:

0.000614

AC XY:

442

AN XY:

719744

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00673

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000730

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000223

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00581

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00104

AC:

126

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2023	The p.Q370K variant (also known as c.1108C>A), located in coding exon 11 of the NEBL gene, results from a C to A substitution at nucleotide position 1108. The glutamine at codon 370 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 12, 2013	The Gln370Lys variant in NEBL has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/8600 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbS NP rs146198369). Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. Additional information is needed to fully assess the clinical signif icance of this variant. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2020	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 01, 2015	Genetic testing comprehensive cardiomyopathy panel: The patient had genetic testing. The test included 77 genes associated with various hereditary cardiomyopathies: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3, BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL, NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43,TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Analysis included both sequencing and array-based comparative genome hybridization to look for duplications and deletions (excluding mitochondrial genes, FKTN, GATAD1). Results showed that a variant was found (see report below): -p.Gln370Lys (c.1108C>A) in the NEBL gene (NM_006393.2) This variant is reviewed in detail below. The labs this variant as a variant of unknown significance. Given lack of case data and it's presence in south Asian control populations we consider this a variant of unknown significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant hasn't been reported with disease previously although it has been reported in general population studies. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.99). The glutamine at codon 370 is not completely conserved across species, (cats have a histidine at that position). No other missense variants have been reported in clinvar in this region of the gene. There are 126 people with variation at codon 370 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent that were not selected for cardiovascular disease (as of October 5, 2015). The frequency in the South Asian population in this cohort is 1/70 people (118/8,254 ppl of South Asian descent). Therefore this is a common variation in the South Asian population with a frequency of >1% of the population. Genetic testing comprehensive arrhythmia panel: The patient had genetic testing at the GeneDx laboratory, using their comprehensive arrhythmia panel. The test included sequencing and duplication/deletion analysis of 30 genes associated with a variety of hereditary arrhythmias: AKAP9, ANK2, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE1, KCNE2, KCNE3, KCNH2 (HERG), KCNJ2, KCNJ5, KCNJ8, KCNQ1, NKX2.5, PKP2, RANGRF (MOG1), RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1,TMEM43 (See report below). Results reported on 8/13/2015 show that no disease-causing variants were found. -

NEBL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2022

This variant is classified as likely 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

M_CAP

Benign

0.022

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.34

Sift

Benign

0.046

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.49

MVP

0.77

MPC

0.027

ClinPred

0.14

GERP RS

5.3

Varity_R

0.64

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over