dbSNP rs71534253: NEBL:c.1008+4C>T (chr10-20852541-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006393.3(NEBL):c.1008+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,608,718 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 11 hom. )

Consequence

NEBL
NM_006393.3 splice_region, intron

Scores

Splicing: ADA: 0.00002403

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.470

Publications

2 publications found

Variant links:

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

NEBL links:

LOC102725112 (HGNC:):

LOC102725112 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 10-20852541-G-A is Benign according to our data. Variant chr10-20852541-G-A is described in ClinVar as Benign. ClinVar VariationId is 164757.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 = 0.00495 (753/152254) while in subpopulation AFR AF = 0.0173 (717/41560). AF 95% confidence interval is 0.0162. There are 9 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 753 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEBL	NM_006393.3	MANE Select	c.1008+4C>T	splice_region intron	N/A	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-39601C>T	intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-39601C>T	intron	N/A	NP_998734.1	Q59FZ8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.1008+4C>T	splice_region intron	N/A	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-39601C>T	intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000863069.1		c.1008+4C>T	splice_region intron	N/A	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.00491

AC:

747

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00114

AC:

285

AN:

250176

AF XY:

0.000872

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000548

AC:

798

AN:

1456464

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

354

AN XY:

724936

show subpopulations

African (AFR)

AF:

0.0183

AC:

611

AN:

33384

American (AMR)

AF:

0.000805

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39640

South Asian (SAS)

AF:

0.000104

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52248

Middle Eastern (MID)

AF:

0.000876

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000722

AC:

AN:

1108246

Other (OTH)

AF:

0.000929

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152254

Hom.:

Cov.:

AF XY:

0.00492

AC XY:

366

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0173

AC:

717

AN:

41560

American (AMR)

AF:

0.00157

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00561

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

NEBL-related disorder (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0010

(source)

DANN

Benign

0.60

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.018

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over