rs727504866

Variant names:

• chr10-20840805-T-C
• rs727504866
• NM_006393.3:c.1272A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006393.3(NEBL):​c.1272A>G​(p.Gly424Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,610,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0430
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-20840805-T-C is Benign according to our data. Variant chr10-20840805-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BS2: High AC in GnomAd4 at 9 AD gene.

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.1272A>G	p.Gly424Gly	synonymous	Exon 13 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.358-27865A>G		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.358-27865A>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.1272A>G	p.Gly424Gly	synonymous	Exon 13 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.358-27865A>G		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.1272A>G	p.Gly424Gly	synonymous	Exon 13 of 28	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249834 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.0000672 AC: 98 AN: 1458596 Hom.: 0 Cov.: 30 AF XY: 0.0000620 AC XY: 45 AN XY: 725806

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.0000224 AC: 1 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1109768

Other (OTH) AF: 0.000149 AC: 9 AN: 60292

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.4
DANN	Benign	0.72
PhyloP100		-0.043

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs727504866; hg19: chr10-21129734;