20-47004952-C-A

Position:

• chr20-47004952-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005244.5(EYA2):​c.166C>A​(p.Arg56Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EYA2 NM_005244.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA2	NM_005244.5	c.166C>A	p.Arg56Ser	missense_variant	4/16	ENST00000327619.10	NP_005235.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA2	ENST00000327619.10	c.166C>A	p.Arg56Ser	missense_variant	4/16	2	NM_005244.5	ENSP00000333640.5
EYA2	ENST00000497062.6	c.166C>A	p.Arg56Ser	missense_variant	4/16	1		ENSP00000417105.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.166C>A (p.R56S) alteration is located in exon 4 (coding exon 3) of the EYA2 gene. This alteration results from a C to A substitution at nucleotide position 166, causing the arginine (R) at amino acid position 56 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.;T;.;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T;T;.;T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.8	L;L;.;L;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.45	N;N;.;D;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.030	D;D;.;D;D;D
Sift4G	Benign	0.066	T;T;T;T;T;T
Polyphen		0.71	P;P;P;.;P;.
Vest4		0.39
MutPred		0.26		Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);.;
MVP		0.86
MPC		0.18
ClinPred		0.84	D
GERP RS		5.5
Varity_R		0.096
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-45633591;