NM_006393.3:c.2149-5G>A

Variant names:

• chr10-20815722-C-T
• rs71578956
• NM_006393.3:c.2149-5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006393.3(NEBL):​c.2149-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,554,908 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (185 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009171
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0330
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-20815722-C-T is Benign according to our data. Variant chr10-20815722-C-T is described in ClinVar as Benign. ClinVar VariationId is 138509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	NM_006393.3	MANE Select	c.2149-5G>A		splice_region intron	N/A	NP_006384.1
	NEBL	NM_001377322.1		c.358-2782G>A		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-2782G>A		intron	N/A	NP_998734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.2149-5G>A		splice_region intron	N/A	ENSP00000366326.4
	NEBL	ENST00000417816.2	TSL:1	c.358-2782G>A		intron	N/A	ENSP00000393896.2
	NEBL	ENST00000493005.5	TSL:1	n.1469-5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152128 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00770 AC: 1929 AN: 250444 AF XY: 0.00709

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00300 AC: 4206 AN: 1402662 Hom.: 185 Cov.: 26 AF XY: 0.00291 AC XY: 2042 AN XY: 701352

African (AFR) AF: 0.000186 AC: 6 AN: 32248

American (AMR) AF: 0.000112 AC: 5 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.0911 AC: 3580 AN: 39288

South Asian (SAS) AF: 0.00337 AC: 287 AN: 85076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53008

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5674

European-Non Finnish (NFE) AF: 0.0000321 AC: 34 AN: 1058530

Other (OTH) AF: 0.00501 AC: 293 AN: 58440

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152246 Hom.: 27 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74418

African (AFR) AF: 0.000530 AC: 22 AN: 41540

American (AMR) AF: 0.000916 AC: 14 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0995 AC: 515 AN: 5176

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.00393

Asia WGS AF: 0.0390 AC: 135 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	NEBL-related disorder (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.5
DANN	Benign	0.55
PhyloP100		0.033
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71578956; hg19: chr10-21104651; COSMIC: COSV65801957;