rs62638654

Variant names:

• chrX-38310661-C-T
• rs62638654
• NM_001034853.2:c.732G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001034853.2(RPGR):​c.732G>A​(p.Lys244Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,209,422 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,062 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., 47 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (6 hom. 1015 hem.)
• Consequence: RPGR NM_001034853.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: -1.22
• Publications: 1 publications found

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

RPGR Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant X-38310661-C-T is Benign according to our data. Variant chrX-38310661-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 98797.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (209/111397) while in subpopulation NFE AF = 0.0032 (170/53083). AF 95% confidence interval is 0.00281. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 209 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. 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
	RPGR	NM_001034853.2	MANE Select	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.729G>A	p.Lys243Lys	synonymous	Exon 7 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-355460C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 211 AN: 111346 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000954

Gnomad ASJ AF: 0.000759

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.000667

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.00269

GnomAD2 exomes AF: 0.00196 AC: 360 AN: 183209 AF XY: 0.00222

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00100

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00273 AC: 2996 AN: 1098025 Hom.: 6 Cov.: 30 AF XY: 0.00279 AC XY: 1015 AN XY: 363399

African (AFR) AF: 0.000379 AC: 10 AN: 26395

American (AMR) AF: 0.00136 AC: 48 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.000980 AC: 19 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00140 AC: 76 AN: 54125

European-Finnish (FIN) AF: 0.000814 AC: 33 AN: 40516

Middle Eastern (MID) AF: 0.00823 AC: 34 AN: 4132

European-Non Finnish (NFE) AF: 0.00313 AC: 2639 AN: 841992

Other (OTH) AF: 0.00297 AC: 137 AN: 46089

GnomAD4 genome AF: 0.00188 AC: 209 AN: 111397 Hom.: 1 Cov.: 23 AF XY: 0.00140 AC XY: 47 AN XY: 33587

African (AFR) AF: 0.000555 AC: 17 AN: 30632

American (AMR) AF: 0.000953 AC: 10 AN: 10492

Ashkenazi Jewish (ASJ) AF: 0.000759 AC: 2 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.000384 AC: 1 AN: 2604

European-Finnish (FIN) AF: 0.000667 AC: 4 AN: 5993

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00320 AC: 170 AN: 53083

Other (OTH) AF: 0.00265 AC: 4 AN: 1508

Alfa AF: 0.00244 Hom.: 25

Bravo AF: 0.00198

EpiCase AF: 0.00464

EpiControl AF: 0.00415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	not provided (3)
-	-	2	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=94/6	polymorphism (auto)

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: rs62638654; hg19: chrX-38169914;