10-21167926-A-T

Variant names:

• chr10-21167926-A-T
• rs1979487
• ENST00000417816.2:c.164+4457T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000417816.2(NEBL):​c.164+4457T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,176 control chromosomes in the GnomAD database, including 1,799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1799 hom., cov: 32)
• Consequence: NEBL ENST00000417816.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEBL	NM_001377322.1	c.164+4457T>A		intron_variant	Intron 2 of 7		NP_001364251.1
NEBL	NM_213569.2	c.164+4457T>A		intron_variant	Intron 2 of 6		NP_998734.1
NEBL	NM_001377323.1	c.116+4457T>A		intron_variant	Intron 2 of 6		NP_001364252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEBL	ENST00000417816.2	c.164+4457T>A		intron_variant	Intron 2 of 6	1		ENSP00000393896.2
NEBL	ENST00000675700.1	n.187+4457T>A		intron_variant	Intron 2 of 6
NEBL	ENST00000675702.1	n.443+4457T>A		intron_variant	Intron 4 of 8
NEBL	ENST00000675747.1	n.224+4457T>A		intron_variant	Intron 2 of 27

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23142 AN: 152058 Hom.: 1793 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.128

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.152 AC: 23161 AN: 152176 Hom.: 1799 Cov.: 32 AF XY: 0.151 AC XY: 11266 AN XY: 74390

African (AFR) AF: 0.138 AC: 5741 AN: 41528

American (AMR) AF: 0.164 AC: 2504 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.226 AC: 1167 AN: 5166

South Asian (SAS) AF: 0.224 AC: 1079 AN: 4808

European-Finnish (FIN) AF: 0.117 AC: 1238 AN: 10604

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10644 AN: 68000

Other (OTH) AF: 0.126 AC: 266 AN: 2114

Alfa AF: 0.0764 Hom.: 81

Bravo AF: 0.152

Asia WGS AF: 0.214 AC: 742 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.9
DANN	Benign	0.71
PhyloP100		-0.031
Mutation Taster		=100/0	polymorphism (auto)

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: rs1979487; hg19: chr10-21456855;