8-10606669-C-G

Variant names:

• chr8-10606669-C-G
• rs12547192
• NM_178857.6:c.*226G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178857.6(RP1L1):​c.*226G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 673,978 control chromosomes in the GnomAD database, including 9,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1680 hom., cov: 34)
  • Exomes 𝑓: 0.16 (8017 hom.)
• Consequence: RP1L1 NM_178857.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520
• Publications: 7 publications found

Genes affected

RP1L1 (HGNC:15946): (RP1 like 1) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two N-terminal doublecortin domains, which bind microtubules and regulate microtubule polymerization, and two C-terminal large repetitive regions, both of which contain a high percentage of glutamine and glutamic acid residues. This protein is a retinal-specific protein. Its exact length varies among individuals due to the presence of a 16aa repeat in the first C-terminal repetitive region. The 16aa repeat is encoded by the highly polymorphic 48-bp repeat, and 1-6 copies of the 16aa repeat have been identified in normal individuals. The current reference sequence shown here has a single copy of the 16aa repeat. This protein and the RP1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Mutations in this gene cause occult macular dystrophy (OMD). [provided by RefSeq, Sep 2010]

RP1L1 Gene-Disease associations (from GenCC):

• occult macular dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• retinitis pigmentosa 88

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• cone dystrophy

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-10606669-C-G is Benign according to our data. Variant chr8-10606669-C-G is described in ClinVar as Benign. ClinVar VariationId is 361196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178857.6. 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
	RP1L1	NM_178857.6	MANE Select	c.*226G>C		3_prime_UTR	Exon 4 of 4	NP_849188.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1L1	ENST00000382483.4	TSL:1 MANE Select	c.*226G>C		3_prime_UTR	Exon 4 of 4	ENSP00000371923.3	Q8IWN7-1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20031 AN: 152130 Hom.: 1679 Cov.: 34

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.161 AC: 83993 AN: 521730 Hom.: 8017 Cov.: 7 AF XY: 0.170 AC XY: 46112 AN XY: 271058

African (AFR) AF: 0.0547 AC: 749 AN: 13696

American (AMR) AF: 0.157 AC: 2639 AN: 16786

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 2099 AN: 13786

East Asian (EAS) AF: 0.183 AC: 5459 AN: 29836

South Asian (SAS) AF: 0.344 AC: 15389 AN: 44728

European-Finnish (FIN) AF: 0.184 AC: 5129 AN: 27890

Middle Eastern (MID) AF: 0.209 AC: 430 AN: 2060

European-Non Finnish (NFE) AF: 0.139 AC: 47848 AN: 345112

Other (OTH) AF: 0.153 AC: 4251 AN: 27836

GnomAD4 genome AF: 0.132 AC: 20029 AN: 152248 Hom.: 1680 Cov.: 34 AF XY: 0.140 AC XY: 10435 AN XY: 74452

African (AFR) AF: 0.0553 AC: 2296 AN: 41556

American (AMR) AF: 0.156 AC: 2390 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 550 AN: 3472

East Asian (EAS) AF: 0.174 AC: 897 AN: 5166

South Asian (SAS) AF: 0.352 AC: 1695 AN: 4820

European-Finnish (FIN) AF: 0.196 AC: 2080 AN: 10608

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9678 AN: 68008

Other (OTH) AF: 0.146 AC: 308 AN: 2110

Alfa AF: 0.124 Hom.: 164

Bravo AF: 0.124

Asia WGS AF: 0.255 AC: 887 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Occult macular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.39
PhyloP100		-0.52
Mutation Taster		=100/0	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: rs12547192; hg19: chr8-10464179;