rs145623359

Positions:

• chr6-64066431-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142800.2(EYS):​c.6632C>T​(p.Ser2211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,549,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.880

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014107585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.6632C>T	p.Ser2211Leu	missense_variant	33/43	ENST00000503581.6
EYS	NM_001292009.2	c.6632C>T	p.Ser2211Leu	missense_variant	33/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.6632C>T	p.Ser2211Leu	missense_variant	33/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.6632C>T	p.Ser2211Leu	missense_variant	33/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000351 AC: 55 AN: 156660 Hom.: 0 AF XY: 0.000253 AC XY: 21 AN XY: 82904

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.000229 AC: 320 AN: 1397196 Hom.: 0 Cov.: 28 AF XY: 0.000225 AC XY: 155 AN XY: 689274

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74426

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.00153

ESP6500AA AF: 0.00434 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000323 AC: 8

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The EYS c.6632C>T (p.Ser2211Leu) missense variant has been reported in two studies and is found in a total of five individuals with autosomal recessive retinitis pigmentosa, including in two siblings in a compound heterozygous state, in two in a heterozygous state, and in one individual who was also heterozygous for a stop-gained variant and another missense variant, though phase is not described (Audo et al. 2010, Barragan et al. 2010). The p.Ser2211Leu variant was absent from 680 controls (Audo et al. 2010, Barragan et al. 2010). The Ser221 residue is conserved in EYS homologues. The p.Ser2211Leu variant is reported at a frequency of 0.00434 in the African American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Ser2211Leu variant is classified as unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinitis pigmentosa 25 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 21069908, 20333770) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.93	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.0040	B;B
Vest4		0.42
MVP		0.20
MPC		0.0099
ClinPred		0.015	T
GERP RS		1.7
Varity_R		0.049
gMVP		0.26

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: rs145623359; hg19: chr6-64776324;