rs41277374

chr10-20889923-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006393.3(NEBL):c.180G>C(p.Lys60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,607,010 control chromosomes in the GnomAD database, including 35 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 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (32 hom.)
• Consequence: NEBL NM_006393.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.102

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008779794).
• BP6: Variant 10-20889923-C-G is Benign according to our data. Variant chr10-20889923-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45486.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=3}. Variant chr10-20889923-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEBL	NM_006393.3	c.180G>C	p.Lys60Asn	missense_variant	3/28	ENST00000377122.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEBL	ENST00000377122.9	c.180G>C	p.Lys60Asn	missense_variant	3/28	1	NM_006393.3

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00648

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00413 AC: 1030 AN: 249578 Hom.: 2 AF XY: 0.00429 AC XY: 578 AN XY: 134754

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00675

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00567 AC: 8250 AN: 1454754 Hom.: 32 Cov.: 28 AF XY: 0.00562 AC XY: 4067 AN XY: 723810

Gnomad4 AFR exome AF: 0.000631

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.00880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74444

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00648

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00627 Hom.: 0

Bravo AF: 0.00393

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00385 AC: 467

EpiCase AF: 0.00655

EpiControl AF: 0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 01, 2016	Based on the minor allele frequency in ExAC we consider this variant likely benign (seen in ~0.6% (423/66580) of European chromosomes). -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	NEBL: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	This variant is associated with the following publications: (PMID: 23299917, 21430528, 24082139, 27186169, 26321576, 25987543, 20951326, 27896284, 26383259) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2015	p.Lys60Asn in exon 3 of NEBL: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (423/66580) of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs41277374). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2013

The p.K60N variant (also known as c.180G>C) is located in coding exon 3 of theNEBLgene. This alteration results from a G to C substitution at nucleotide position 180. The lysine at codon 60 is replaced by asparagine, an amino acid with some similar properties. ​​In an initial publication associating NEBLwith dilated cardiomyopathy (DCM), this alteration was identified in a cohort of 260 individuals with DCM and absent in 600 control alleles. This alteration was found to be de novoin a proband with adult onset DCM. Authors subsequently developed a transgenic mouse model, and founder mice with this alteration developed severe heart failure at one year old. Embryos with this alteration did not survive, presenting the possibility of embryonic lethality with the p.K60N alteration(Purevjav E etal. J Am Coll Cardiol. 2010;56(18):1493-1502).However, a later publication denotes that the presence and frequency of this alteration in a large population based database from the Exome Sequencing Project (ESP) creates uncertainty regarding its pathogenicity (Andreasen C etal. Eur J Hum Genet. 2013;21(9):918-928). This variant was previously reported in dbSNP asrs41277374. Based on data from the NHLBI Exome Sequencing Project (ESP), the C-allele has an overall frequency of approximately0.52% (67/12998), having been observed in 0.71% (61/8594) of European American alleles, and in 0.14% (6/4404)of African American alleles studied. Based on data from the 1000 Genomes Project, the C-allele has an overall frequency of approximately0.18% (4/2184). The highest observed frequency was 1.12% (2/178) of Britishchromosomes studied. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence for this variant is conflicting and limited at this time, its clinical significance remains unclear. -

NEBL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.50		Loss of methylation at K60 (P = 0.0203);.;
MVP		0.72
MPC		0.12
ClinPred		0.044	T
GERP RS		1.9
Varity_R		0.67
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41277374; hg19: chr10-21178852;