rs397517859

Positions:

• chr1-77926600-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_144573.4(NEXN):​c.677del​(p.Ser226TyrfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEXN NM_144573.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.677del	p.Ser226TyrfsTer2	frameshift_variant	7/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.677del	p.Ser226TyrfsTer2	frameshift_variant	7/13	1	NM_144573.4	ENSP00000333938	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 08, 2012

Variant classified as Uncertain Significance - Favor Pathogenic. The Ser226fs va riant (NEXN) has not been reported in the literature nor previously identified b y our laboratory. This frameshift variant is predicted to alter the protein?s a mino acid sequence beginning at position 226 and lead to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Although the severe nature of the change increases the likelihood that the variant is pathogenic, the NEXN gene has not been widely studied and the spectrum of variants leading to disease is not well defined. To date, only a small number of missense variants in this gene have been reported in individuals with cardiomyopathy. In summary, it has not yet been established whether loss of function variants in the NEXN gene can cause disease and the cli nical significance of this variant can therefore not be determined at this time. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397517859; hg19: chr1-78392285;