rs371431782

Variant names:

• chr1-77917694-C-A
• rs371431782
• NM_144573.4:c.156C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-77917694-C-A
• chr1-77917694-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144573.4(NEXN):​c.156C>A​(p.Asp52Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D52D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NEXN NM_144573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.46
• Publications: 2 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), PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023033708).

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.156C>A	p.Asp52Glu	missense	Exon 3 of 13	NP_653174.3
	NEXN	NM_001172309.2		c.28-266C>A		intron	N/A	NP_001165780.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXN	ENST00000334785.12	TSL:1 MANE Select	c.156C>A	p.Asp52Glu	missense	Exon 3 of 13	ENSP00000333938.7
	NEXN	ENST00000401035.7	TSL:1	c.28-266C>A		intron	N/A	ENSP00000383814.3
	NEXN	ENST00000951152.1		c.156C>A	p.Asp52Glu	missense	Exon 4 of 14	ENSP00000621211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459526 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726122

African (AFR) AF: 0.0000300 AC: 1 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110642

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.010
DANN	Benign	0.69
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.85	N
PhyloP100		-2.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.070
Sift	Benign	0.71	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.14		Gain of helix (P = 0.062)
MVP		0.23
MPC		0.046
ClinPred		0.041	T
GERP RS		-4.8
PromoterAI		-0.019	Neutral
Varity_R		0.047
gMVP		0.032
Mutation Taster		=85/15	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: rs371431782; hg19: chr1-78383379;