8-54621040-G-C

Variant names:

• chr8-54621040-G-C
• NM_006269.2:c.74G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006269.2(RP1):​c.74G>C​(p.Arg25Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2	c.74G>C	p.Arg25Pro	missense_variant	Exon 2 of 4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000220676.2	c.74G>C	p.Arg25Pro	missense_variant	Exon 2 of 4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.74G>C	p.Arg25Pro	missense_variant	Exon 2 of 29	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.74G>C	p.Arg25Pro	missense_variant	Exon 2 of 23	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	.;D;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	.;D;.
Vest4		0.50
MutPred		0.29		Gain of glycosylation at R25 (P = 0.0043);Gain of glycosylation at R25 (P = 0.0043);Gain of glycosylation at R25 (P = 0.0043);
MVP		0.61
MPC		0.25
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-55533600;