chr10-20888214-GA-G

Variant names:

• chr10-20888214-GA-G
• rs57918610
• NM_006393.3:c.259-8delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006393.3(NEBL):​c.259-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,403,682 control chromosomes in the GnomAD database, including 44 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (23 hom.)
• Consequence: NEBL NM_006393.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.367
• 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 -16 ACMG points.

• BP6: Variant 10-20888214-GA-G is Benign according to our data. Variant chr10-20888214-GA-G is described in ClinVar as Benign. ClinVar VariationId is 179196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (1544/113452) while in subpopulation AFR AF = 0.0403 (1381/34234). AF 95% confidence interval is 0.0386. There are 21 homozygotes in GnomAd4. There are 751 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1544 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.259-8delT		splice_region intron	N/A	NP_006384.1	O76041-1
	NEBL	NM_001377322.1		c.357+73457delT		intron	N/A	NP_001364251.1
	NEBL	NM_213569.2		c.357+73457delT		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.259-8delT		splice_region intron	N/A	ENSP00000366326.4	O76041-1
	NEBL	ENST00000417816.2	TSL:1	c.357+73457delT		intron	N/A	ENSP00000393896.2	O76041-2
	NEBL	ENST00000863069.1		c.259-8delT		splice_region intron	N/A	ENSP00000533128.1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 1539 AN: 113342 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.0290

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000443

Gnomad SAS AF: 0.00176

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00256 AC: 546 AN: 213600 AF XY: 0.00201

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000759

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00162 AC: 2096 AN: 1290230 Hom.: 23 Cov.: 23 AF XY: 0.00153 AC XY: 989 AN XY: 646474

African (AFR) AF: 0.0324 AC: 941 AN: 29080

American (AMR) AF: 0.00361 AC: 148 AN: 41024

Ashkenazi Jewish (ASJ) AF: 0.0000417 AC: 1 AN: 23958

East Asian (EAS) AF: 0.000350 AC: 13 AN: 37120

South Asian (SAS) AF: 0.00147 AC: 115 AN: 78162

European-Finnish (FIN) AF: 0.0000794 AC: 4 AN: 50400

Middle Eastern (MID) AF: 0.000953 AC: 5 AN: 5248

European-Non Finnish (NFE) AF: 0.000739 AC: 718 AN: 971674

Other (OTH) AF: 0.00282 AC: 151 AN: 53564

GnomAD4 genome AF: 0.0136 AC: 1544 AN: 113452 Hom.: 21 Cov.: 31 AF XY: 0.0137 AC XY: 751 AN XY: 54638

African (AFR) AF: 0.0403 AC: 1381 AN: 34234

American (AMR) AF: 0.00583 AC: 60 AN: 10292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2902

East Asian (EAS) AF: 0.000444 AC: 2 AN: 4502

South Asian (SAS) AF: 0.00177 AC: 6 AN: 3386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00114 AC: 57 AN: 50036

Other (OTH) AF: 0.0123 AC: 19 AN: 1550

Alfa AF: 0.000499 Hom.: 11

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.37
Mutation Taster		=100/0	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: rs57918610; hg19: chr10-21177143;