dbSNP rs71578938: NEBL:c.1117-6T>G (chr10-20845374-A-C) – 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.1117-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,469,078 control chromosomes in the GnomAD database, including 14 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 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 6 hom. )

Consequence

NEBL
NM_006393.3 splice_region, intron

Scores

Splicing: ADA: 0.3635

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.90

Publications

3 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=-0.7).

BP6

Variant 10-20845374-A-C is Benign according to our data. Variant chr10-20845374-A-C is described in ClinVar as Benign. ClinVar VariationId is 45474.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 = 0.00494 (753/152286) while in subpopulation AFR AF = 0.0164 (680/41560). AF 95% confidence interval is 0.0153. There are 8 homozygotes in GnomAd4. There are 362 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.1117-6T>G	splice_region intron	N/A	NP_006384.1	O76041-1
NEBL	NM_001377322.1		c.358-32434T>G	intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-32434T>G	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.1117-6T>G	splice_region intron	N/A	ENSP00000366326.4	O76041-1
NEBL	ENST00000417816.2	TSL:1	c.358-32434T>G	intron	N/A	ENSP00000393896.2	O76041-2
NEBL	ENST00000863069.1		c.1117-6T>G	splice_region intron	N/A	ENSP00000533128.1

Frequencies

GnomAD3 genomes

AF:

0.00492

AC:

748

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

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:

0.000485

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00154

AC:

385

AN:

249592

AF XY:

0.00126

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.000532

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000889

AC:

1171

AN:

1316792

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

552

AN XY:

662748

show subpopulations

African (AFR)

AF:

0.0187

AC:

570

AN:

30556

American (AMR)

AF:

0.00155

AC:

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.000160

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

38920

South Asian (SAS)

AF:

0.000564

AC:

AN:

83362

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

52802

Middle Eastern (MID)

AF:

0.00458

AC:

AN:

5458

European-Non Finnish (NFE)

AF:

0.000352

AC:

345

AN:

980742

Other (OTH)

AF:

0.00191

AC:

106

AN:

55500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00494

AC:

753

AN:

152286

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

362

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0164

AC:

680

AN:

41560

American (AMR)

AF:

0.00235

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68004

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

101

134

168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00233

Hom.:

Bravo

AF:

0.00549

Asia WGS

AF:

0.00376

AC:

AN:

3476

EpiCase

AF:

0.000764

EpiControl

AF:

0.000891

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)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

1.9

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.36

dbscSNV1_RF

Benign

0.56

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