chr6-63999014-A-C

Variant names:

• chr6-63999014-A-C
• rs66502009
• NM_001142800.2:c.6834+61T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142800.2(EYS):​c.6834+61T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,027,904 control chromosomes in the GnomAD database, including 71,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7796 hom., cov: 31)
  • Exomes 𝑓: 0.38 (63692 hom.)
• Consequence: EYS NM_001142800.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.422
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• EYS-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• retinitis pigmentosa 25

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

LOC107986608 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-63999014-A-C is Benign according to our data. Variant chr6-63999014-A-C is described in ClinVar as [Benign]. Clinvar id is 1175356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.6834+61T>G		intron_variant	Intron 34 of 42	ENST00000503581.6	NP_001136272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.6834+61T>G		intron_variant	Intron 34 of 42	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.6834+61T>G		intron_variant	Intron 34 of 43	1		ENSP00000359655.3
EYS	ENST00000398580.3	c.147+61T>G		intron_variant	Intron 2 of 9	5		ENSP00000381585.3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45781 AN: 151904 Hom.: 7797 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.344

GnomAD4 exome AF: 0.375 AC: 328599 AN: 875882 Hom.: 63692 AF XY: 0.379 AC XY: 170786 AN XY: 450548

African (AFR) AF: 0.146 AC: 3057 AN: 21010

American (AMR) AF: 0.232 AC: 7728 AN: 33348

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 8799 AN: 21310

East Asian (EAS) AF: 0.260 AC: 8580 AN: 33024

South Asian (SAS) AF: 0.424 AC: 28549 AN: 67344

European-Finnish (FIN) AF: 0.315 AC: 15289 AN: 48532

Middle Eastern (MID) AF: 0.365 AC: 1695 AN: 4642

European-Non Finnish (NFE) AF: 0.396 AC: 239833 AN: 606152

Other (OTH) AF: 0.372 AC: 15069 AN: 40520

GnomAD4 genome AF: 0.301 AC: 45788 AN: 152022 Hom.: 7796 Cov.: 31 AF XY: 0.299 AC XY: 22221 AN XY: 74282

African (AFR) AF: 0.147 AC: 6099 AN: 41480

American (AMR) AF: 0.276 AC: 4211 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1419 AN: 3468

East Asian (EAS) AF: 0.269 AC: 1386 AN: 5162

South Asian (SAS) AF: 0.420 AC: 2024 AN: 4816

European-Finnish (FIN) AF: 0.301 AC: 3168 AN: 10538

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26105 AN: 67968

Other (OTH) AF: 0.339 AC: 716 AN: 2110

Alfa AF: 0.334 Hom.: 1153

Bravo AF: 0.292

Asia WGS AF: 0.296 AC: 1030 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 25 Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.82
DANN	Benign	0.84
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs66502009; hg19: chr6-64708907; COSMIC: COSV65474781;