chr2-17592082-A-G

Position:

• chr2-17592082-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003385.5(VSNL1):​c.8A>G​(p.Lys3Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VSNL1 NM_003385.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, null
• BP4: Computational evidence support a benign effect (MetaRNN=0.40319398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSNL1	NM_003385.5	c.8A>G	p.Lys3Arg	missense_variant	2/4	ENST00000295156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSNL1	ENST00000295156.9	c.8A>G	p.Lys3Arg	missense_variant	2/4	1	NM_003385.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Ambry Genetics

Dec 30, 2023

The c.8A>G (p.K3R) alteration is located in exon 2 (coding exon 1) of the VSNL1 gene. This alteration results from a A to G substitution at nucleotide position 8, causing the lysine (K) at amino acid position 3 to be replaced by an arginine (R). 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	Benign	0.13
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;N;N;D;N
REVEL	Benign	0.28
Sift	Uncertain	0.017	D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		0.47	P;.;P;.;P
Vest4		0.49
MutPred		0.21		Loss of ubiquitination at K3 (P = 0.0141);Loss of ubiquitination at K3 (P = 0.0141);Loss of ubiquitination at K3 (P = 0.0141);Loss of ubiquitination at K3 (P = 0.0141);Loss of ubiquitination at K3 (P = 0.0141);
MVP		0.36
MPC		1.3
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.30
gMVP		0.78

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: rs1664603979; hg19: chr2-17773349;