chr2-218429286-G-C

Position:

• chr2-218429286-G-C

Variant summary

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

The NM_007127.3(VIL1):​c.569G>C​(p.Gly190Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VIL1 NM_007127.3 missense, splice_region
• Scores: Splicing: ADA: 0.0007601
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.63

Genes affected

VIL1 (HGNC:12690): (villin 1) This gene encodes a member of a family of calcium-regulated actin-binding proteins. This protein represents a dominant part of the brush border cytoskeleton which functions in the capping, severing, and bundling of actin filaments. Two mRNAs of 2.7 kb and 3.5 kb have been observed; they result from utilization of alternate poly-adenylation signals present in the terminal exon. [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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VIL1	NM_007127.3	c.569G>C	p.Gly190Ala	missense_variant, splice_region_variant	7/20	ENST00000248444.10	NP_009058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VIL1	ENST00000248444.10	c.569G>C	p.Gly190Ala	missense_variant, splice_region_variant	7/20	1	NM_007127.3	ENSP00000248444.5
VIL1	ENST00000440053.1	c.569G>C	p.Gly190Ala	missense_variant, splice_region_variant	6/9	1		ENSP00000409270.1
VIL1	ENST00000392114.6	c.-183-182G>C		intron_variant		2		ENSP00000375962.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Nov 13, 2024

The c.569G>C (p.G190A) alteration is located in exon 7 (coding exon 6) of the VIL1 gene. This alteration results from a G to C substitution at nucleotide position 569, causing the glycine (G) at amino acid position 190 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.49
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.082	B;.
Vest4		0.73
MutPred		0.74		Loss of disorder (P = 0.131);Loss of disorder (P = 0.131);
MVP		0.53
MPC		0.26
ClinPred		0.53	D
GERP RS		4.8
Varity_R		0.11
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.050		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: rs756272645; hg19: chr2-219294009;