Genetic Variant NM_006393.3:c.2057T>C (chr10-20817691-A-G) – 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.2057T>C(p.Val686Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,608,220 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V686I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0083 ( 25 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 24 hom. )

Consequence

NEBL
NM_006393.3 missense, splice_region

Scores

Splicing: ADA: 0.009522

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.79

Publications

8 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:

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 (MetaRNN=0.0070819557).

BP6

Variant 10-20817691-A-G is Benign according to our data. Variant chr10-20817691-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45490.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 = 0.00827 (1259/152244) while in subpopulation AFR AF = 0.0287 (1190/41532). AF 95% confidence interval is 0.0273. There are 25 homozygotes in GnomAd4. There are 611 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1259 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	HGVSp	Effect	Exon Rank	Protein
NEBL	NM_006393.3	MANE Select	c.2057T>C	p.Val686Ala	missense splice_region	Exon 21 of 28	NP_006384.1
NEBL	NM_001377322.1		c.358-4751T>C		intron	N/A	NP_001364251.1
NEBL	NM_213569.2		c.358-4751T>C		intron	N/A	NP_998734.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEBL	ENST00000377122.9	TSL:1 MANE Select	c.2057T>C	p.Val686Ala	missense splice_region	Exon 21 of 28	ENSP00000366326.4
NEBL	ENST00000417816.2	TSL:1	c.358-4751T>C		intron	N/A	ENSP00000393896.2
NEBL	ENST00000493005.5	TSL:1	n.1377T>C		splice_region non_coding_transcript_exon	Exon 8 of 12

Frequencies

GnomAD3 genomes

AF:

0.00829

AC:

1261

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

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:

0.000162

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00251

AC:

630

AN:

250940

AF XY:

0.00176

show subpopulations

Gnomad AFR exome

AF:

0.0322

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000951

AC:

1385

AN:

1455976

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

584

AN XY:

724702

show subpopulations

African (AFR)

AF:

0.0303

AC:

1010

AN:

33320

American (AMR)

AF:

0.00224

AC:

100

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1106730

Other (OTH)

AF:

0.00243

AC:

146

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

138

206

275

344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00827

AC:

1259

AN:

152244

Hom.:

Cov.:

AF XY:

0.00821

AC XY:

611

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0287

AC:

1190

AN:

41532

American (AMR)

AF:

0.00314

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68028

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

183

244

305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00326

Hom.:

Bravo

AF:

0.00923

ESP6500AA

AF:

0.0325

AC:

143

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00297

AC:

360

Asia WGS

AF:

0.00231

AC:

AN:

3476

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

NEBL-related disorder (1)

not provided (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0075

Eigen

Benign

-0.018

Eigen_PC

Benign

0.071

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

3.1

PhyloP100

7.8

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.2

REVEL

Benign

0.16

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

0.0020

Vest4

0.46

MVP

0.60

MPC

0.017

ClinPred

0.059

GERP RS

5.0

PromoterAI

0.012

Neutral

(source)

Varity_R

0.17

gMVP

0.12

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0095

dbscSNV1_RF

Benign

0.094

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