8-10691348-T-G

Position:

• chr8-10691348-T-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8orf74	NM_001040032.2	c.242-6251T>G		intron_variant		ENST00000304519.10
C8orf74	XM_047421493.1	c.299-6251T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8orf74	ENST00000304519.10	c.242-6251T>G		intron_variant		1	NM_001040032.2	P1
C8orf74	ENST00000521818.1	c.*417T>G		3_prime_UTR_variant	3/3	5
C8orf74	ENST00000523289.5	c.*133+4077T>G		intron_variant, NMD_transcript_variant		2
RP1L1	ENST00000329335.3	n.231+20609A>C		intron_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.0869

Gnomad4 ASJ exome AF: 0.00814

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0860

Gnomad4 FIN exome AF: 0.0373

Gnomad4 NFE exome AF: 0.00636

Gnomad4 OTH exome AF: 0.0686

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

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0601

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.123

Alfa AF: 0.106 Hom.: 579

Bravo AF: 0.191

Asia WGS AF: 0.119 AC: 415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.084
DANN	Benign	0.41

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: rs10097570; hg19: chr8-10548858;