19-12825830-A-C

Position:

• chr19-12825830-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001270441.2(RTBDN):​c.566T>G​(p.Val189Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RTBDN NM_001270441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.141

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]

(HGNC:):

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08494097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTBDN	NM_001270441.2	c.566T>G	p.Val189Gly	missense_variant	6/6	ENST00000674343.2	NP_001257370.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTBDN	ENST00000674343.2	c.566T>G	p.Val189Gly	missense_variant	6/6		NM_001270441.2	ENSP00000501410	A2
	ENST00000588469.1	n.120A>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 589 AN: 145922 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00264

Gnomad ASJ AF: 0.00358

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00197

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0600 AC: 55235 AN: 920448 Hom.: 0 Cov.: 44 AF XY: 0.0549 AC XY: 25961 AN XY: 472940

Gnomad4 AFR exome AF: 0.0630

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.0579

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0668

Gnomad4 NFE exome AF: 0.0687

Gnomad4 OTH exome AF: 0.0610

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00405 AC: 591 AN: 146074 Hom.: 0 Cov.: 31 AF XY: 0.00447 AC XY: 318 AN XY: 71160

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00250

Gnomad4 ASJ AF: 0.00358

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00850

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.00195

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.662T>G (p.V221G) alteration is located in exon 7 (coding exon 7) of the RTBDN gene. This alteration results from a T to G substitution at nucleotide position 662, causing the valine (V) at amino acid position 221 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.87
DEOGEN2	Benign	0.0095	T;.;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.32	T;T;T;.;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.085	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	.;.;N;N;.;.
REVEL	Benign	0.022
Sift	Uncertain	0.0030	.;.;D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		0.0090	B;.;B;B;.;.
Vest4		0.10
MutPred		0.27		Loss of stability (P = 0.0025);.;.;Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);.;
MVP		0.27
MPC		0.44
ClinPred		0.13	T
GERP RS		0.71
Varity_R		0.12
gMVP		0.57

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: rs1969269718; hg19: chr19-12936644;