rs397517852

Positions:

• chr1-77942738-C-A
• chr1-77942738-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000334785.12(NEXN):​c.1937C>A​(p.Pro646Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P646P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEXN ENST00000334785.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000334785.12
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4	c.1937C>A	p.Pro646Gln	missense_variant	13/13	ENST00000334785.12	NP_653174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12	c.1937C>A	p.Pro646Gln	missense_variant	13/13	1	NM_144573.4	ENSP00000333938	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 01, 2011

The Pro646Gln variant has not been previously reported but has been identified b y our laboratory in 1 individual with HCM. Proline (Pro) at position 646 is high ly conserved across evolutionarily distant species, increasing the likelihood th at a change would not be tolerated. In addition, computational tools (AlignGVGD, PolyPhen2, and SIFT) predict that this change will impact the protein, though t heir accuracy is unknown. Although this data increases the likelihood that this variant is pathogenic, it should be noted that the NEXN gene has not yet been wi dely sequenced. It therefore remains possible that this variant will turn out to be common in the general population once a larger number of individuals have be en sequenced. In summary, additional data is needed to determine the clinical si gnificance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.54		.;Gain of sheet (P = 0.0827);
MVP		0.59
MPC		0.31
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs397517852; hg19: chr1-78408423;