NM_006269.2:c.5G>T

Variant names:

• chr8-54620971-G-T
• rs552496407
• NM_006269.2:c.5G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006269.2(RP1):​c.5G>T​(p.Ser2Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,262 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.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RP1 NM_006269.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18861046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2	c.5G>T	p.Ser2Ile	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.5G>T	p.Ser2Ile	missense_variant	Exon 2 of 4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.5G>T	p.Ser2Ile	missense_variant	Exon 2 of 29	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.5G>T	p.Ser2Ile	missense_variant	Exon 2 of 23	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74438

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	.;D;.
REVEL	Benign	0.16
Sift	Benign	0.043	.;D;.
Sift4G	Benign	0.074	.;T;.
Polyphen		1.0	.;D;.
Vest4		0.34
MutPred		0.17		Loss of glycosylation at S2 (P = 0.0103);Loss of glycosylation at S2 (P = 0.0103);Loss of glycosylation at S2 (P = 0.0103);
MVP		0.57
MPC		0.051
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.59

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: rs552496407; hg19: chr8-55533531;