8-10691348-T-G

Variant names:

• chr8-10691348-T-G
• rs10097570
• NM_001040032.2:c.242-6251T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040032.2(C8orf74):​c.242-6251T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 181,272 control chromosomes in the GnomAD database, including 6,989 homozygotes. 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 0.17 (6395 hom., cov: 33)
  • Exomes 𝑓: 0.094 (594 hom.)
• Consequence: C8orf74 NM_001040032.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• Publications: 1 publications found

Genes affected

C8orf74 (HGNC:32296): (chromosome 8 open reading frame 74)

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
• retinitis pigmentosa

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

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

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040032.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8orf74	NM_001040032.2	MANE Select	c.242-6251T>G		intron	N/A	NP_001035121.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8orf74	ENST00000304519.10	TSL:1 MANE Select	c.242-6251T>G		intron	N/A	ENSP00000307129.5
	C8orf74	ENST00000521818.1	TSL:5	c.*417T>G		3_prime_UTR	Exon 3 of 3	ENSP00000429505.1
	RP1L1	ENST00000329335.3	TSL:2	n.231+20609A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25804 AN: 151998 Hom.: 6366 Cov.: 33

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0594

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.0937 AC: 2733 AN: 29156 Hom.: 594 Cov.: 0 AF XY: 0.0840 AC XY: 1294 AN XY: 15404

African (AFR) AF: 0.661 AC: 1662 AN: 2516

American (AMR) AF: 0.0869 AC: 291 AN: 3348

Ashkenazi Jewish (ASJ) AF: 0.00814 AC: 5 AN: 614

East Asian (EAS) AF: 0.125 AC: 291 AN: 2324

South Asian (SAS) AF: 0.0860 AC: 265 AN: 3080

European-Finnish (FIN) AF: 0.0373 AC: 23 AN: 616

Middle Eastern (MID) AF: 0.103 AC: 8 AN: 78

European-Non Finnish (NFE) AF: 0.00636 AC: 97 AN: 15254

Other (OTH) AF: 0.0686 AC: 91 AN: 1326

GnomAD4 genome AF: 0.170 AC: 25889 AN: 152116 Hom.: 6395 Cov.: 33 AF XY: 0.168 AC XY: 12486 AN XY: 74382

African (AFR) AF: 0.543 AC: 22485 AN: 41396

American (AMR) AF: 0.102 AC: 1555 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.110 AC: 570 AN: 5168

South Asian (SAS) AF: 0.0601 AC: 290 AN: 4824

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68020

Other (OTH) AF: 0.123 AC: 259 AN: 2114

Alfa AF: 0.0888 Hom.: 911

Bravo AF: 0.191

Asia WGS AF: 0.119 AC: 415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.084
DANN	Benign	0.41
PhyloP100		-1.9
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: rs10097570; hg19: chr8-10548858;