rs532565487

Variant names:

• chr10-20787250-G-A
• rs532565487
• NM_006393.3:c.2820C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006393.3(NEBL):​c.2820C>T​(p.His940His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,613,500 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: NEBL NM_006393.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.16
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 10-20787250-G-A is Benign according to our data. Variant chr10-20787250-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.16 with no splicing effect.
• BS2: High AC in GnomAd4 at 13 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.2820C>T	p.His940His	synonymous	Exon 27 of 28	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.681C>T	p.His227His	synonymous	Exon 7 of 8	NP_001364251.1
	NEBL	NM_213569.2		c.588C>T	p.His196His	synonymous	Exon 6 of 7	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.2820C>T	p.His940His	synonymous	Exon 27 of 28	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.588C>T	p.His196His	synonymous	Exon 6 of 7	ENSP00000393896.2	O76041-2
	NEBL	ENST00000676125.1		c.617C>T	p.Thr206Ile	missense	Exon 7 of 8	ENSP00000501594.1	A0A6Q8PF21

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000551 AC: 138 AN: 250544 AF XY: 0.000754

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000272 AC: 398 AN: 1461262 Hom.: 4 Cov.: 31 AF XY: 0.000415 AC XY: 302 AN XY: 726880

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00440 AC: 379 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111684

Other (OTH) AF: 0.000298 AC: 18 AN: 60364

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000905 Hom.: 0

Bravo AF: 0.0000340

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.5
DANN	Benign	0.54
PhyloP100		2.2
Mutation Taster		=95/5	polymorphism

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: rs532565487; hg19: chr10-21076179;