2-218425738-C-T

Variant names:

• chr2-218425738-C-T
• rs201270409
• NM_007127.3:c.274C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_007127.3(VIL1):​c.274C>T​(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,614,140 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (10 hom.)
• Consequence: VIL1 NM_007127.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00400

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01359567).
• BP6: Variant 2-218425738-C-T is Benign according to our data. Variant chr2-218425738-C-T is described in ClinVar as [Benign]. Clinvar id is 3033712.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIL1	NM_007127.3	c.274C>T	p.Arg92Trp	missense_variant	Exon 4 of 20	ENST00000248444.10	NP_009058.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIL1	ENST00000248444.10	c.274C>T	p.Arg92Trp	missense_variant	Exon 4 of 20	1	NM_007127.3	ENSP00000248444.5
VIL1	ENST00000440053.1	c.274C>T	p.Arg92Trp	missense_variant	Exon 3 of 9	1		ENSP00000409270.1
VIL1	ENST00000454069.5	c.274C>T	p.Arg92Trp	missense_variant	Exon 4 of 6	3		ENSP00000412657.1
VIL1	ENST00000392114.6	c.-183-3730C>T		intron_variant	Intron 1 of 14	2		ENSP00000375962.2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 251242 Hom.: 5 AF XY: 0.00152 AC XY: 207 AN XY: 135804

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00813

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000521 AC: 761 AN: 1461846 Hom.: 10 Cov.: 31 AF XY: 0.000802 AC XY: 583 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00798

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000831 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

VIL1-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	0.051
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.90	P;.;.
Vest4		0.52
MutPred		0.55		Loss of disorder (P = 0.0442);Loss of disorder (P = 0.0442);Loss of disorder (P = 0.0442);
MVP		0.76
MPC		0.20
ClinPred		0.073	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.65

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: rs201270409; hg19: chr2-219290461;