6-64591931-T-C

Position:

• chr6-64591931-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142800.2(EYS):​c.3936A>G​(p.Thr1312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,532,292 control chromosomes in the GnomAD database, including 13,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (946 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12650 hom.)
• Consequence: EYS NM_001142800.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.00400

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-64591931-T-C is Benign according to our data. Variant chr6-64591931-T-C is described in ClinVar as [Benign]. Clinvar id is 93607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64591931-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.004 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.3936A>G	p.Thr1312=	synonymous_variant	26/43	ENST00000503581.6
EYS	NM_001292009.2	c.3936A>G	p.Thr1312=	synonymous_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.3936A>G	p.Thr1312=	synonymous_variant	26/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.3936A>G	p.Thr1312=	synonymous_variant	26/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15754 AN: 152028 Hom.: 946 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.114 AC: 16802 AN: 147292 Hom.: 1099 AF XY: 0.115 AC XY: 8955 AN XY: 78090

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0769

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.0975

Gnomad FIN exome AF: 0.0794

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.130 AC: 179718 AN: 1380146 Hom.: 12650 Cov.: 34 AF XY: 0.130 AC XY: 88117 AN XY: 678948

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.0772

Gnomad4 EAS exome AF: 0.144

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0798

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.104 AC: 15763 AN: 152146 Hom.: 946 Cov.: 32 AF XY: 0.102 AC XY: 7582 AN XY: 74392

Gnomad4 AFR AF: 0.0460

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0738

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0999

Alfa AF: 0.117 Hom.: 454

Bravo AF: 0.108

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -

Retinitis pigmentosa Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinitis pigmentosa 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.59
DANN	Benign	0.28

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: rs12662610; hg19: chr6-65301824;