rs1006363

Variant names:

• chr10-20819448-C-T
• rs1006363
• NM_006393.3:c.2031G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006393.3(NEBL):​c.2031G>A​(p.Arg677Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,702 control chromosomes in the GnomAD database, including 66,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4653 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61714 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0920
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-20819448-C-T is Benign according to our data. Variant chr10-20819448-C-T is described in ClinVar as Benign. ClinVar VariationId is 45489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 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.2031G>A	p.Arg677Arg	synonymous	Exon 20 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-6508G>A		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-6508G>A		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.2031G>A	p.Arg677Arg	synonymous	Exon 20 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-6508G>A		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000493005.5	TSL:1	n.631G>A		non_coding_transcript_exon	Exon 7 of 12

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33874 AN: 151958 Hom.: 4653 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.193

GnomAD2 exomes AF: 0.247 AC: 62107 AN: 251314 AF XY: 0.250

Gnomad AFR exome AF: 0.0627

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.284 AC: 414474 AN: 1461626 Hom.: 61714 Cov.: 37 AF XY: 0.281 AC XY: 204568 AN XY: 727142

African (AFR) AF: 0.0522 AC: 1746 AN: 33476

American (AMR) AF: 0.172 AC: 7683 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 5127 AN: 26128

East Asian (EAS) AF: 0.221 AC: 8773 AN: 39690

South Asian (SAS) AF: 0.189 AC: 16329 AN: 86258

European-Finnish (FIN) AF: 0.375 AC: 20024 AN: 53408

Middle Eastern (MID) AF: 0.122 AC: 705 AN: 5766

European-Non Finnish (NFE) AF: 0.305 AC: 338989 AN: 1111798

Other (OTH) AF: 0.250 AC: 15098 AN: 60384

GnomAD4 genome AF: 0.223 AC: 33870 AN: 152076 Hom.: 4653 Cov.: 32 AF XY: 0.226 AC XY: 16784 AN XY: 74348

African (AFR) AF: 0.0641 AC: 2658 AN: 41494

American (AMR) AF: 0.205 AC: 3125 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 684 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1169 AN: 5166

South Asian (SAS) AF: 0.189 AC: 911 AN: 4814

European-Finnish (FIN) AF: 0.388 AC: 4094 AN: 10560

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20428 AN: 67986

Other (OTH) AF: 0.191 AC: 403 AN: 2110

Alfa AF: 0.242 Hom.: 8421

Bravo AF: 0.201

Asia WGS AF: 0.182 AC: 635 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.271

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	-0.55
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		0.092
PromoterAI		0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs1006363; hg19: chr10-21108377; COSMIC: COSV65801322; COSMIC: COSV65801322;