2-218429401-C-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007127.3(VIL1):c.684C>A(p.His228Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,614,126 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H228Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (51 hom.)
• Consequence: VIL1 NM_007127.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005089283).
• BP6: Variant 2-218429401-C-A is Benign according to our data. Variant chr2-218429401-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 378854.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIL1	NM_007127.3	c.684C>A	p.His228Gln	missense_variant	7/20	ENST00000248444.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIL1	ENST00000248444.10	c.684C>A	p.His228Gln	missense_variant	7/20	1	NM_007127.3	P1
VIL1	ENST00000440053.1	c.684C>A	p.His228Gln	missense_variant	6/9	1
VIL1	ENST00000392114.6	c.-183-67C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 922 AN: 152228 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00717 AC: 1802 AN: 251280 Hom.: 22 AF XY: 0.00747 AC XY: 1015 AN XY: 135850

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00675

Gnomad NFE exome AF: 0.00796

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00656 AC: 9591 AN: 1461780 Hom.: 51 Cov.: 31 AF XY: 0.00649 AC XY: 4723 AN XY: 727204

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.00645

Gnomad4 NFE exome AF: 0.00661

Gnomad4 OTH exome AF: 0.00747

GnomAD4 genome AF: 0.00603 AC: 919 AN: 152346 Hom.: 6 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74492

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00803 Hom.: 10

Bravo AF: 0.00612

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00708 AC: 860

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.0104

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.34
Dann	Benign	0.34
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.051
Sift	Benign	0.63	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0010	B;.
Vest4		0.22
MutPred		0.33		Loss of catalytic residue at L230 (P = 0.0516);Loss of catalytic residue at L230 (P = 0.0516);
MVP		0.17
MPC		0.19
ClinPred		0.00044	T
GERP RS		0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs148353573; hg19: chr2-219294124;