14-74245180-C-T

Variant names:

• chr14-74245180-C-T
• rs35435463
• NM_182894.3:c.471C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182894.3(VSX2):​c.471C>T​(p.Ser157Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,612,744 control chromosomes in the GnomAD database, including 194,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S157S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (13854 hom., cov: 27)
  • Exomes 𝑓: 0.49 (181047 hom.)
• Consequence: VSX2 NM_182894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.399
• Publications: 14 publications found

Genes affected

VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

VSX2 Gene-Disease associations (from GenCC):

• isolated microphthalmia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• microphthalmia, isolated, with coloboma 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• microphthalmia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-74245180-C-T is Benign according to our data. Variant chr14-74245180-C-T is described in ClinVar as Benign. ClinVar VariationId is 167840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182894.3. 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
	VSX2	NM_182894.3	MANE Select	c.471C>T	p.Ser157Ser	synonymous	Exon 3 of 5	NP_878314.1	P58304

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX2	ENST00000261980.3	TSL:1 MANE Select	c.471C>T	p.Ser157Ser	synonymous	Exon 3 of 5	ENSP00000261980.2	P58304

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57787 AN: 151214 Hom.: 13850 Cov.: 27

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.429 AC: 107675 AN: 250814 AF XY: 0.431

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.0530

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.485 AC: 708830 AN: 1461412 Hom.: 181047 Cov.: 53 AF XY: 0.482 AC XY: 350037 AN XY: 726970

African (AFR) AF: 0.0986 AC: 3300 AN: 33470

American (AMR) AF: 0.496 AC: 22164 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10243 AN: 26126

East Asian (EAS) AF: 0.0879 AC: 3491 AN: 39694

South Asian (SAS) AF: 0.344 AC: 29670 AN: 86240

European-Finnish (FIN) AF: 0.570 AC: 30378 AN: 53336

Middle Eastern (MID) AF: 0.307 AC: 1771 AN: 5766

European-Non Finnish (NFE) AF: 0.523 AC: 581058 AN: 1111726

Other (OTH) AF: 0.443 AC: 26755 AN: 60372

GnomAD4 genome AF: 0.382 AC: 57803 AN: 151332 Hom.: 13854 Cov.: 27 AF XY: 0.385 AC XY: 28473 AN XY: 73872

African (AFR) AF: 0.117 AC: 4821 AN: 41292

American (AMR) AF: 0.454 AC: 6904 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1342 AN: 3464

East Asian (EAS) AF: 0.0694 AC: 357 AN: 5144

South Asian (SAS) AF: 0.317 AC: 1508 AN: 4754

European-Finnish (FIN) AF: 0.587 AC: 6148 AN: 10474

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.521 AC: 35262 AN: 67702

Other (OTH) AF: 0.371 AC: 777 AN: 2096

Alfa AF: 0.455 Hom.: 8804

Bravo AF: 0.360

Asia WGS AF: 0.219 AC: 761 AN: 3478

EpiCase AF: 0.495

EpiControl AF: 0.497

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Isolated microphthalmia 2 (3)
-	-	2	Microphthalmia, isolated, with coloboma 3 (2)
-	-	2	not provided (2)
-	-	1	Microphthalmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.80
PhyloP100		0.40
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35435463; hg19: chr14-74711883; COSMIC: COSV56216854;