chr1-77942798-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_144573.4(NEXN):c.1997C>A(p.Thr666Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,610,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T666A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.33

Publications

1 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: MODERATE 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)

NEXN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2894702).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000103 (15/1458388) while in subpopulation EAS AF = 0.000328 (13/39646). AF 95% confidence interval is 0.000193. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 15 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.1997C>A	p.Thr666Asn	missense	Exon 13 of 13	NP_653174.3
	NEXN	NM_001172309.2		c.1805C>A	p.Thr602Asn	missense	Exon 12 of 12	NP_001165780.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEXN	ENST00000334785.12	TSL:1 MANE Select	c.1997C>A	p.Thr666Asn	missense	Exon 13 of 13	ENSP00000333938.7
NEXN	ENST00000342754.5	TSL:1	c.1694C>A	p.Thr565Asn	missense	Exon 9 of 10	ENSP00000343928.5
NEXN	ENST00000951152.1		c.1997C>A	p.Thr666Asn	missense	Exon 14 of 14	ENSP00000621211.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000322

AC:

AN:

248472

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000446

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458388

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.000328

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109348

Other (OTH)

AF:

0.0000332

AC:

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000225

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

Eigen

Benign

-0.0090

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.038

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.87

PhyloP100

3.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

REVEL

Benign

0.050

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.013

Polyphen

0.44

Vest4

0.54

MutPred

0.37

Loss of sheet (P = 0.1501)

MVP

0.72

MPC

0.078

ClinPred

0.18

GERP RS

3.9

Varity_R

0.46

gMVP

0.64

Mutation Taster

=56/44

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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