rs6138482

Variant names:

• chr20-25078806-C-T
• rs6138482
• ENST00000376707.4:c.650G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-25078806-C-T
• chr20-25078806-C-A
• chr20-25078806-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199425.3(VSX1):​c.650G>A​(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,780 control chromosomes in the GnomAD database, including 36,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2832 hom., cov: 32)
  • Exomes 𝑓: 0.20 (33364 hom.)
• Consequence: VSX1 NM_199425.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.159
• Publications: 55 publications found

Genes affected

VSX1 (HGNC:12723): (visual system homeobox 1) The protein encoded by this gene contains a paired-like homeodomain and binds to the core of the locus control region of the red/green visual pigment gene cluster. The encoded protein may regulate expression of the cone opsin genes early in development. Mutations in this gene can cause posterior polymorphous corneal dystrophy and keratoconus. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

VSX1 Gene-Disease associations (from GenCC):

• posterior polymorphous corneal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• keratoconus 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• craniofacial anomalies and anterior segment dysgenesis syndrome

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• posterior polymorphous corneal dystrophy 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.990231E-5).
• BP6: Variant 20-25078806-C-T is Benign according to our data. Variant chr20-25078806-C-T is described in ClinVar as Benign. ClinVar VariationId is 1684215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199425.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	NM_014588.6	MANE Select	c.627+23G>A		intron	N/A	NP_055403.2
	VSX1	NM_199425.3		c.650G>A	p.Arg217His	missense	Exon 3 of 3	NP_955457.1	Q9NZR4-2
	VSX1	NM_001256272.2		c.627+23G>A		intron	N/A	NP_001243201.1	Q9NZR4-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	ENST00000376707.4	TSL:1	c.650G>A	p.Arg217His	missense	Exon 3 of 3	ENSP00000365897.3	Q9NZR4-2
	VSX1	ENST00000376709.9	TSL:1 MANE Select	c.627+23G>A		intron	N/A	ENSP00000365899.3	Q9NZR4-1
	VSX1	ENST00000429762.7	TSL:1	c.627+23G>A		intron	N/A	ENSP00000401690.3	Q9NZR4-8

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25082 AN: 151790 Hom.: 2834 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.211 AC: 52980 AN: 251472 AF XY: 0.210

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.510

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.204 AC: 297675 AN: 1461874 Hom.: 33364 Cov.: 71 AF XY: 0.203 AC XY: 147591 AN XY: 727240

African (AFR) AF: 0.0318 AC: 1063 AN: 33480

American (AMR) AF: 0.224 AC: 10023 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4713 AN: 26136

East Asian (EAS) AF: 0.544 AC: 21590 AN: 39700

South Asian (SAS) AF: 0.173 AC: 14937 AN: 86258

European-Finnish (FIN) AF: 0.192 AC: 10276 AN: 53416

Middle Eastern (MID) AF: 0.189 AC: 1091 AN: 5768

European-Non Finnish (NFE) AF: 0.200 AC: 222199 AN: 1111996

Other (OTH) AF: 0.195 AC: 11783 AN: 60396

GnomAD4 genome AF: 0.165 AC: 25081 AN: 151906 Hom.: 2832 Cov.: 32 AF XY: 0.170 AC XY: 12646 AN XY: 74234

African (AFR) AF: 0.0395 AC: 1637 AN: 41440

American (AMR) AF: 0.220 AC: 3354 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3468

East Asian (EAS) AF: 0.518 AC: 2666 AN: 5146

South Asian (SAS) AF: 0.176 AC: 842 AN: 4784

European-Finnish (FIN) AF: 0.201 AC: 2120 AN: 10546

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13212 AN: 67946

Other (OTH) AF: 0.191 AC: 402 AN: 2108

Alfa AF: 0.190 Hom.: 10595

Bravo AF: 0.164

TwinsUK AF: 0.207 AC: 767

ALSPAC AF: 0.191 AC: 736

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.198 AC: 1700

ExAC AF: 0.206 AC: 25047

Asia WGS AF: 0.300 AC: 1043 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.193

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Keratoconus 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.5
DANN	Benign	0.86
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.000080	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.16
PROVEAN	Benign	2.6	N
REVEL	Benign	0.18
Sift	Benign	0.049	D
Polyphen		0.0080	B
Vest4		0.012
ClinPred		0.0018	T
GERP RS		-4.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6138482; hg19: chr20-25059442; COSMIC: COSV65021866; COSMIC: COSV65021866;