6-64066431-G-A

Position:

chr6-64066431-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 0.880

Variant links:

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]

EYS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a domain Laminin G-like 2 (size 194) in uniprot entity EYS_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_001142800.2

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	Protein	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.6632C>T	p.Ser2211Leu	missense_variant	33/43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 linkuse as main transcript	c.6632C>T	p.Ser2211Leu	missense_variant	33/44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.6632C>T	p.Ser2211Leu	missense_variant	33/43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.6632C>T	p.Ser2211Leu	missense_variant	33/44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152132

Hom.:

Cov.:

show subpopulations

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:

AN:

156660

Hom.:

AF XY:

0.000253

AC XY:

AN XY:

82904

show subpopulations

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.:

Cov.:

AF XY:

0.000225

AC XY:

155

AN XY:

689274

show subpopulations

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.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74426

show subpopulations

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.:

Bravo

AF:

0.00153

ESP6500AA

AF:

0.00434

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000323

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

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:1Benign:1

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

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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) -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.25

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over