chr14-21326018-G-C

Variant names:

• chr14-21326018-G-C
• rs181758389
• NM_020366.4:c.2555G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020366.4(RPGRIP1):​c.2555G>C​(p.Arg852Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R852Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• Publications: 0 publications found

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12758136).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. 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
	RPGRIP1	NM_020366.4	MANE Select	c.2555G>C	p.Arg852Pro	missense	Exon 17 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.1481G>C	p.Arg494Pro	missense	Exon 7 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.796+1293G>C		intron	N/A	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2555G>C	p.Arg852Pro	missense	Exon 17 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.980G>C	p.Arg327Pro	missense	Exon 5 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.689-1605G>C		intron	N/A	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	9.4
DANN	Benign	0.95
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.075
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.57
Sift	Benign	0.25	T
Sift4G	Benign	0.21	T
Polyphen		0.0030	B
Vest4		0.30
MutPred		0.45		Loss of helix (P = 0.079)
MVP		0.63
MPC		0.24
ClinPred		0.096	T
GERP RS		-2.1
Varity_R		0.36
gMVP		0.80
Mutation Taster		=52/48	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: rs181758389; hg19: chr14-21794177;