rs199917913

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_144573.4(NEXN):c.856C>T(p.Arg286Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R286Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.443

Publications

2 publications found

Variant links:

Genes affected

NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

NEXN Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: STRONG Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1CC
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy 20
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NEXN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03680852).

BP6

Variant 1-77926884-C-T is Benign according to our data. Variant chr1-77926884-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201919.

BS2

High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144573.4. 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
	NEXN	NM_144573.4	MANE Select	c.856C>T	p.Arg286Trp	missense	Exon 8 of 13	NP_653174.3	Q0ZGT2-1
	NEXN	NM_001172309.2		c.664C>T	p.Arg222Trp	missense	Exon 7 of 12	NP_001165780.1	Q0ZGT2-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEXN	ENST00000334785.12	TSL:1 MANE Select	c.856C>T	p.Arg286Trp	missense	Exon 8 of 13	ENSP00000333938.7	Q0ZGT2-1
NEXN	ENST00000342754.5	TSL:1	c.553C>T	p.Arg185Trp	missense	Exon 4 of 10	ENSP00000343928.5	H7BXY5
NEXN	ENST00000401035.7	TSL:1	c.664C>T	p.Arg222Trp	missense	Exon 7 of 9	ENSP00000383814.3	E7ETM8

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000133

AC:

AN:

247848

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461586

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111956

Other (OTH)

AF:

0.000248

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000921

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41364

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

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:

0.000293

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000272

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000994

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 (1)

not provided (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.15

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.6

PhyloP100

0.44

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.10

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.33

MVP

0.75

MPC

0.14

ClinPred

0.35

GERP RS

2.5

Varity_R

0.051

gMVP

0.044

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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