19-12825921-C-G

Variant names:

• chr19-12825921-C-G
• rs537117488
• NM_001270441.2:c.475G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001270441.2(RTBDN):​c.475G>C​(p.Gly159Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,589,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: RTBDN NM_001270441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

RTBDN (HGNC:30310): (retbindin) This gene was first identified in a study of human eye tissues. The protein encoded by this gene is preferentially expressed in the retina and may play a role in binding retinoids and other carotenoids as it shares homology with riboflavin binding proteins. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

RTBDN-AS1 (HGNC:58174):

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270441.2. 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
	RTBDN	NM_001270441.2	MANE Select	c.475G>C	p.Gly159Arg	missense	Exon 6 of 6	NP_001257370.2	Q9BSG5-1
	RTBDN	NM_031429.3		c.571G>C	p.Gly191Arg	missense	Exon 7 of 7	NP_113617.1	Q9BSG5-2
	RTBDN	NM_001270442.2		c.493G>C	p.Gly165Arg	missense	Exon 6 of 6	NP_001257371.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTBDN	ENST00000674343.2	MANE Select	c.475G>C	p.Gly159Arg	missense	Exon 6 of 6	ENSP00000501410.1	Q9BSG5-1
	RTBDN	ENST00000322912.9	TSL:1	c.571G>C	p.Gly191Arg	missense	Exon 7 of 7	ENSP00000326253.4	Q9BSG5-2
	RTBDN	ENST00000592204.5	TSL:1	c.505G>C	p.Gly169Arg	missense	Exon 6 of 6	ENSP00000466765.1	Q9BSG5-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000474 AC: 11 AN: 231904 AF XY: 0.0000395

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 24 AN: 1436932 Hom.: 0 Cov.: 35 AF XY: 0.0000126 AC XY: 9 AN XY: 711572

African (AFR) AF: 0.00 AC: 0 AN: 32762

American (AMR) AF: 0.000144 AC: 6 AN: 41782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.0000714 AC: 6 AN: 84086

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00000820 AC: 9 AN: 1096952

Other (OTH) AF: 0.0000338 AC: 2 AN: 59100

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.87		Gain of helix (P = 0.0854)
MVP		0.80
MPC		0.74
ClinPred		0.71	D
GERP RS		4.6
Varity_R		0.58
gMVP		0.96
Mutation Taster		=96/4	polymorphism

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: rs537117488; hg19: chr19-12936735;