6-64912625-C-T

Position:

• chr6-64912625-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_001142800.2(EYS):​c.2500G>A​(p.Val834Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,551,080 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V834L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: -0.186

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 Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001142800.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.015545726).
• BP6: Variant 6-64912625-C-T is Benign according to our data. Variant chr6-64912625-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64912625-C-T is described in Lovd as [Likely_benign]. Variant chr6-64912625-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.2500G>A	p.Val834Ile	missense_variant	16/43	ENST00000503581.6
EYS	NM_001292009.2	c.2500G>A	p.Val834Ile	missense_variant	16/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.2500G>A	p.Val834Ile	missense_variant	16/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.2500G>A	p.Val834Ile	missense_variant	16/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152036 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000736

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000519 AC: 81 AN: 155948 Hom.: 0 AF XY: 0.000484 AC XY: 40 AN XY: 82588

Gnomad AFR exome AF: 0.00694

Gnomad AMR exome AF: 0.000893

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000880

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000217 AC: 304 AN: 1398926 Hom.: 1 Cov.: 33 AF XY: 0.000207 AC XY: 143 AN XY: 689930

Gnomad4 AFR exome AF: 0.00706

Gnomad4 AMR exome AF: 0.000953

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.00231 AC: 351 AN: 152154 Hom.: 1 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74404

Gnomad4 AFR AF: 0.00766

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000393 Hom.: 2

Bravo AF: 0.00265

ESP6500AA AF: 0.0101 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000968 AC: 24

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	EYS: BP4 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	See Variant Classification Assertion Criteria. -

Retinitis pigmentosa 25 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 15, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 20, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.61
DANN	Benign	0.89
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.51	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.010	B;.
Vest4		0.26
MVP		0.19
MPC		0.010
ClinPred		0.0011	T
GERP RS		-0.50
Varity_R		0.034
gMVP		0.80

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: rs112464110; hg19: chr6-65622518;