chr10-20852540-T-C

Variant names:

• chr10-20852540-T-C
• rs703089
• NM_006393.3:c.1008+5A>G

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.1008+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,608,006 control chromosomes in the GnomAD database, including 788,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73304 hom., cov: 31)
  • Exomes 𝑓: 0.99 (714861 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Scores: Splicing: ADA: 0.0007574
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.412
• Publications: 12 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

LOC102725112 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-20852540-T-C is Benign according to our data. Variant chr10-20852540-T-C is described in ClinVar as Benign. ClinVar VariationId is 45471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.1008+5A>G		splice_region intron	N/A	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-39600A>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-39600A>G		intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEBL	ENST00000377122.9	TSL:1 MANE Select	c.1008+5A>G		splice_region intron	N/A	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-39600A>G		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.1008+5A>G		splice_region intron	N/A	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.981 AC: 149204 AN: 152158 Hom.: 73261 Cov.: 31

Gnomad AFR AF: 0.980

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.988

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.973

GnomAD2 exomes AF: 0.964 AC: 241060 AN: 250054 AF XY: 0.971

Gnomad AFR exome AF: 0.980

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 0.909

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.990 AC: 1441662 AN: 1455730 Hom.: 714861 Cov.: 33 AF XY: 0.991 AC XY: 718287 AN XY: 724684

African (AFR) AF: 0.982 AC: 32780 AN: 33368

American (AMR) AF: 0.822 AC: 36736 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26095 AN: 26112

East Asian (EAS) AF: 0.914 AC: 36215 AN: 39616

South Asian (SAS) AF: 0.991 AC: 85369 AN: 86152

European-Finnish (FIN) AF: 1.00 AC: 52117 AN: 52118

Middle Eastern (MID) AF: 0.998 AC: 5690 AN: 5702

European-Non Finnish (NFE) AF: 1.00 AC: 1107263 AN: 1107750

Other (OTH) AF: 0.986 AC: 59397 AN: 60218

GnomAD4 genome AF: 0.980 AC: 149303 AN: 152276 Hom.: 73304 Cov.: 31 AF XY: 0.979 AC XY: 72915 AN XY: 74472

African (AFR) AF: 0.980 AC: 40721 AN: 41538

American (AMR) AF: 0.903 AC: 13807 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.902 AC: 4663 AN: 5172

South Asian (SAS) AF: 0.988 AC: 4767 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67999 AN: 68040

Other (OTH) AF: 0.973 AC: 2054 AN: 2112

Alfa AF: 0.988 Hom.: 194212

Bravo AF: 0.971

Asia WGS AF: 0.952 AC: 3312 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	13
DANN	Benign	0.24
PhyloP100		-0.41
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 5

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

Other links and lift over

dbSNP: rs703089; hg19: chr10-21141469; COSMIC: COSV65804997;