NM_001142800.2:c.5244A>C

Variant names:

• chr6-64590623-T-G
• rs57312007
• NM_001142800.2:c.5244A>C

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.5244A>C​(p.Leu1748Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,551,050 control chromosomes in the GnomAD database, including 12,752 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (921 hom., cov: 33)
  • Exomes 𝑓: 0.13 (11831 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.162
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030450225).
• BP6: Variant 6-64590623-T-G is Benign according to our data. Variant chr6-64590623-T-G is described in ClinVar as Benign. ClinVar VariationId is 93616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.5244A>C	p.Leu1748Phe	missense	Exon 26 of 43	NP_001136272.1	Q5T1H1-1
	EYS	NM_001292009.2		c.5244A>C	p.Leu1748Phe	missense	Exon 26 of 44	NP_001278938.1	Q5T1H1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.5244A>C	p.Leu1748Phe	missense	Exon 26 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.5244A>C	p.Leu1748Phe	missense	Exon 26 of 44	ENSP00000359655.3	Q5T1H1-3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15866 AN: 152094 Hom.: 922 Cov.: 33

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0203

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0861

GnomAD2 exomes AF: 0.102 AC: 15658 AN: 153662 AF XY: 0.104

Gnomad AFR exome AF: 0.0647

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.0102

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.126 AC: 175844 AN: 1398838 Hom.: 11831 Cov.: 35 AF XY: 0.125 AC XY: 86071 AN XY: 689922

African (AFR) AF: 0.0614 AC: 1939 AN: 31572

American (AMR) AF: 0.0503 AC: 1795 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 2513 AN: 25152

East Asian (EAS) AF: 0.0400 AC: 1430 AN: 35722

South Asian (SAS) AF: 0.0961 AC: 7613 AN: 79224

European-Finnish (FIN) AF: 0.177 AC: 8716 AN: 49256

Middle Eastern (MID) AF: 0.0506 AC: 288 AN: 5696

European-Non Finnish (NFE) AF: 0.135 AC: 145283 AN: 1078546

Other (OTH) AF: 0.108 AC: 6267 AN: 57976

GnomAD4 genome AF: 0.104 AC: 15861 AN: 152212 Hom.: 921 Cov.: 33 AF XY: 0.104 AC XY: 7750 AN XY: 74424

African (AFR) AF: 0.0664 AC: 2759 AN: 41554

American (AMR) AF: 0.0605 AC: 924 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3466

East Asian (EAS) AF: 0.0203 AC: 105 AN: 5168

South Asian (SAS) AF: 0.0902 AC: 436 AN: 4834

European-Finnish (FIN) AF: 0.181 AC: 1920 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9132 AN: 67982

Other (OTH) AF: 0.0857 AC: 181 AN: 2112

Alfa AF: 0.122 Hom.: 3947

Bravo AF: 0.0929

TwinsUK AF: 0.129 AC: 477

ALSPAC AF: 0.141 AC: 542

ESP6500AA AF: 0.0824 AC: 114

ESP6500EA AF: 0.133 AC: 422

ExAC AF: 0.0973 AC: 2065

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Retinitis pigmentosa (2)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.16
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.11
Sift	Benign	0.31	T
Sift4G	Benign	0.15	T
Polyphen		0.40	B
Vest4		0.023
MutPred		0.34		Loss of sheet (P = 0.0357)
MPC		0.059
ClinPred		0.0044	T
GERP RS		-7.6
Varity_R		0.049
gMVP		0.0084
Mutation Taster		=88/12	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: rs57312007; hg19: chr6-65300516; COSMIC: COSV107370117; COSMIC: COSV107370117;