19-10021323-T-C

Variant names:

• chr19-10021323-T-C
• rs1644731
• NM_015725.4:c.605T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015725.4(RDH8):​c.605T>C​(p.Met202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,613,596 control chromosomes in the GnomAD database, including 196,388 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (21383 hom., cov: 30)
  • Exomes 𝑓: 0.48 (175005 hom.)
• Consequence: RDH8 NM_015725.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461
• Publications: 42 publications found

Genes affected

RDH8 (HGNC:14423): (retinol dehydrogenase 8) This gene encodes a member of the short-chain dehydrogenase/reductase family. The encoded protein catalyzes the reduction of all-trans-retinal to all-trans-retinol, the first reaction step of the rhodopsin regeneration pathway. This enzymatic reaction is the rate-limiting step in the visual cycle. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.462228E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015725.4. 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
	RDH8	NM_015725.4	MANE Select	c.605T>C	p.Met202Thr	missense	Exon 5 of 6	NP_056540.3	Q9NYR8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH8	ENST00000591589.3	TSL:1 MANE Select	c.605T>C	p.Met202Thr	missense	Exon 5 of 6	ENSP00000466058.2	Q9NYR8
	RDH8	ENST00000651512.1		c.665T>C	p.Met222Thr	missense	Exon 5 of 6	ENSP00000498711.1	K7ELF7
	RDH8	ENST00000587782.1	TSL:2	c.49T>C	p.Trp17Arg	missense	Exon 2 of 3	ENSP00000465773.1	K7EKT5

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79587 AN: 151658 Hom.: 21352 Cov.: 30

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.523

GnomAD2 exomes AF: 0.524 AC: 131845 AN: 251406 AF XY: 0.527

Gnomad AFR exome AF: 0.623

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.552

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.505

GnomAD4 exome AF: 0.484 AC: 708170 AN: 1461818 Hom.: 175005 Cov.: 55 AF XY: 0.489 AC XY: 355428 AN XY: 727224

African (AFR) AF: 0.628 AC: 21019 AN: 33480

American (AMR) AF: 0.580 AC: 25923 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12831 AN: 26136

East Asian (EAS) AF: 0.566 AC: 22463 AN: 39700

South Asian (SAS) AF: 0.665 AC: 57333 AN: 86256

European-Finnish (FIN) AF: 0.523 AC: 27911 AN: 53418

Middle Eastern (MID) AF: 0.555 AC: 3199 AN: 5768

European-Non Finnish (NFE) AF: 0.456 AC: 507044 AN: 1111950

Other (OTH) AF: 0.504 AC: 30447 AN: 60388

GnomAD4 genome AF: 0.525 AC: 79680 AN: 151778 Hom.: 21383 Cov.: 30 AF XY: 0.531 AC XY: 39404 AN XY: 74178

African (AFR) AF: 0.618 AC: 25552 AN: 41378

American (AMR) AF: 0.552 AC: 8420 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1687 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2831 AN: 5144

South Asian (SAS) AF: 0.677 AC: 3262 AN: 4820

European-Finnish (FIN) AF: 0.547 AC: 5750 AN: 10518

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30538 AN: 67898

Other (OTH) AF: 0.528 AC: 1112 AN: 2106

Alfa AF: 0.478 Hom.: 78049

Bravo AF: 0.526

TwinsUK AF: 0.460 AC: 1706

ALSPAC AF: 0.471 AC: 1817

ESP6500AA AF: 0.616 AC: 2715

ESP6500EA AF: 0.454 AC: 3907

ExAC AF: 0.520 AC: 63135

Asia WGS AF: 0.637 AC: 2217 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.17
DANN	Benign	0.39
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.048	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.46
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.56	T
Vest4		0.0060
MPC		0.17
ClinPred		0.0044	T
GERP RS		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1644731; hg19: chr19-10131999; COSMIC: COSV50675294; COSMIC: COSV50675294;