rs368812830

Variant names:

• chr1-77936024-G-A
• rs368812830
• NM_144573.4:c.1453G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-77936024-G-A
• chr1-77936024-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_144573.4(NEXN):​c.1453G>A​(p.Glu485Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: NEXN NM_144573.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 10.0
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• BS2: High AC in GnomAd4 at 9 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.1453G>A	p.Glu485Lys	missense	Exon 11 of 13	NP_653174.3	Q0ZGT2-1
	NEXN	NM_001172309.2		c.1261G>A	p.Glu421Lys	missense	Exon 10 of 12	NP_001165780.1	Q0ZGT2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXN	ENST00000334785.12	TSL:1 MANE Select	c.1453G>A	p.Glu485Lys	missense	Exon 11 of 13	ENSP00000333938.7	Q0ZGT2-1
	NEXN	ENST00000342754.5	TSL:1	c.1150G>A	p.Glu384Lys	missense	Exon 7 of 10	ENSP00000343928.5	H7BXY5
	NEXN	ENST00000951152.1		c.1453G>A	p.Glu485Lys	missense	Exon 12 of 14	ENSP00000621211.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000522 AC: 13 AN: 248962 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1460932 Hom.: 0 Cov.: 32 AF XY: 0.0000482 AC XY: 35 AN XY: 726812

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000448 AC: 2 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1111440

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.0000497 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	2	-	Cardiovascular phenotype (2)
-	2	-	Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 (2)
-	1	-	Cardiomyopathy (1)
-	1	-	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.044	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.087	T
Polyphen		1.0	D
Vest4		0.84
MVP		0.87
MPC		0.34
ClinPred		0.30	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.34
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs368812830; hg19: chr1-78401709;