2-17649528-G-A

Variant names:

• chr2-17649528-G-A
• NM_003385.5:c.281G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003385.5(VSNL1):​c.281G>A​(p.Arg94Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VSNL1 NM_003385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

Genes affected

VSNL1 (HGNC:12722): (visinin like 1) This gene is a member of the visinin/recoverin subfamily of neuronal calcium sensor proteins. The encoded protein is strongly expressed in granule cells of the cerebellum where it associates with membranes in a calcium-dependent manner and modulates intracellular signaling pathways of the central nervous system by directly or indirectly regulating the activity of adenylyl cyclase. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

LOC124908054 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSNL1	NM_003385.5	c.281G>A	p.Arg94Lys	missense_variant	Exon 3 of 4	ENST00000295156.9	NP_003376.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSNL1	ENST00000295156.9	c.281G>A	p.Arg94Lys	missense_variant	Exon 3 of 4	1	NM_003385.5	ENSP00000295156.4
VSNL1	ENST00000404666.6	c.281G>A	p.Arg94Lys	missense_variant	Exon 3 of 4	3		ENSP00000384014.1

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

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281G>A (p.R94K) alteration is located in exon 3 (coding exon 2) of the VSNL1 gene. This alteration results from a G to A substitution at nucleotide position 281, causing the arginine (R) at amino acid position 94 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;.;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D;.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M;.;M;.;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.019	D;T;D;D;D
Sift4G	Uncertain	0.050	T;T;T;T;T
Polyphen		0.86	P;.;P;.;P
Vest4		0.63
MutPred		0.54		Gain of ubiquitination at R94 (P = 0.0198);Gain of ubiquitination at R94 (P = 0.0198);Gain of ubiquitination at R94 (P = 0.0198);Gain of ubiquitination at R94 (P = 0.0198);Gain of ubiquitination at R94 (P = 0.0198);
MVP		0.46
MPC		1.8
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-17830795;