10-20889960-G-T

Position:

• chr10-20889960-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006393.3(NEBL):​c.154-11C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,516,648 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (31 hom.)
• Consequence: NEBL NM_006393.3 intron
• Scores: Splicing: ADA: 0.001037
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.551

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-20889960-G-T is Benign according to our data. Variant chr10-20889960-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 45483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-20889960-G-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEBL	NM_006393.3	c.154-11C>A		intron_variant		ENST00000377122.9	NP_006384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000377122.9	c.154-11C>A		intron_variant		1	NM_006393.3	ENSP00000366326.4

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00299 AC: 733 AN: 245262 Hom.: 1 AF XY: 0.00305 AC XY: 403 AN XY: 132330

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.000308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000492

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00547 AC: 7469 AN: 1364398 Hom.: 31 Cov.: 21 AF XY: 0.00528 AC XY: 3611 AN XY: 683274

Gnomad4 AFR exome AF: 0.000799

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000474

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000636

Gnomad4 FIN exome AF: 0.000676

Gnomad4 NFE exome AF: 0.00675

Gnomad4 OTH exome AF: 0.00562

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74438

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00576

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00315

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2015	c.154-11C>A in intron 2 of NEBL: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (307/64874) European chromoso mes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs41277376). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 01, 2024	- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.13
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: rs41277376; hg19: chr10-21178889;