chr20-47089289-A-G

Position:

• chr20-47089289-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005244.5(EYA2):​c.712A>G​(p.Thr238Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,154 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0074 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: EYA2 NM_005244.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.260

Genes affected

EYA2 (HGNC:3520): (EYA transcriptional coactivator and phosphatase 2) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may be post-translationally modified and may play a role in eye development. A similar protein in mice can act as a transcriptional activator. Alternative splicing results in multiple transcript variants, but the full-length natures of all of these variants have not yet been determined. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033411086).
• BP6: Variant 20-47089289-A-G is Benign according to our data. Variant chr20-47089289-A-G is described in ClinVar as [Benign]. Clinvar id is 782065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00745 (1134/152298) while in subpopulation AFR AF= 0.0247 (1028/41560). AF 95% confidence interval is 0.0235. There are 17 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA2	NM_005244.5	c.712A>G	p.Thr238Ala	missense_variant	8/16	ENST00000327619.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA2	ENST00000327619.10	c.712A>G	p.Thr238Ala	missense_variant	8/16	2	NM_005244.5	P1

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1117 AN: 152180 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00240 AC: 604 AN: 251388 Hom.: 8 AF XY: 0.00184 AC XY: 250 AN XY: 135862

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1461856 Hom.: 15 Cov.: 30 AF XY: 0.000958 AC XY: 697 AN XY: 727230

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00745 AC: 1134 AN: 152298 Hom.: 17 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74484

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00243 Hom.: 5

Bravo AF: 0.00813

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.4
DANN	Benign	0.91
DEOGEN2	Benign	0.044	T;.;T;.;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.40	T;T;T;T;.;T
MetaRNN	Benign	0.0033	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L;L;.;.;.;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.83	N;N;.;.;N;N
REVEL	Benign	0.24
Sift	Benign	0.27	T;T;.;.;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;.
Vest4		0.11
MVP		0.55
MPC		0.11
ClinPred		0.00087	T
GERP RS		-3.3
Varity_R		0.028
gMVP		0.29

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: rs866936; hg19: chr20-45717928; COSMIC: COSV99047246;