dbSNP rs374260457: NEXN:p.Ala343Ala (chr1-77929480-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_144573.4(NEXN):c.1029G>A(p.Ala343Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,612,778 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

NEXN
NM_144573.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.283

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.033).

BP6

Variant 1-77929480-G-A is Benign according to our data. Variant chr1-77929480-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.283 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000223 (34/152284) while in subpopulation AFR AF = 0.00065 (27/41564). AF 95% confidence interval is 0.000458. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 34 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.1029G>A	p.Ala343Ala	synonymous	Exon 9 of 13	NP_653174.3	Q0ZGT2-1
	NEXN	NM_001172309.2		c.837G>A	p.Ala279Ala	synonymous	Exon 8 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.1029G>A	p.Ala343Ala	synonymous	Exon 9 of 13	ENSP00000333938.7	Q0ZGT2-1
NEXN	ENST00000342754.5	TSL:1	c.726G>A	p.Ala242Ala	synonymous	Exon 5 of 10	ENSP00000343928.5	H7BXY5
NEXN	ENST00000401035.7	TSL:1	c.837G>A	p.Ala279Ala	synonymous	Exon 8 of 9	ENSP00000383814.3	E7ETM8

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000101

AC:

AN:

246840

AF XY:

0.0000820

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000389

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1460494

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726550

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33430

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000227

AC:

AN:

39624

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4970

European-Non Finnish (NFE)

AF:

0.0000549

AC:

AN:

1111772

Other (OTH)

AF:

0.000116

AC:

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000223

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000226

Hom.:

Bravo

AF:

0.000238

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

-0.28

Mutation Taster

=100/0

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

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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