8-10698004-A-C

Position:

chr8-10698004-A-C

Variant summary

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

The NM_001040032.2(C8orf74):c.647A>C(p.Gln216Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000441 in 1,473,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

C8orf74
NM_001040032.2 missense, splice_region

Scores

Splicing: ADA: 0.9930

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.13

Variant links:

Genes affected

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

C8orf74 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8orf74	NM_001040032.2 linkuse as main transcript	c.647A>C	p.Gln216Pro	missense_variant, splice_region_variant	3/4	ENST00000304519.10
C8orf74	XM_047421493.1 linkuse as main transcript	c.704A>C	p.Gln235Pro	missense_variant, splice_region_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
C8orf74	ENST00000304519.10 linkuse as main transcript	c.647A>C	p.Gln216Pro	missense_variant, splice_region_variant	3/4	1	NM_001040032.2	P1
C8orf74	ENST00000523289.5 linkuse as main transcript	c.*539A>C		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	4/5	2
RP1L1	ENST00000329335.3 linkuse as main transcript	n.231+13953T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

88642

Hom.:

AF XY:

0.0000864

AC XY:

AN XY:

46270

show subpopulations

Gnomad AFR exome

AF:

0.000753

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000366

GnomAD4 exome

AF:

0.0000265

AC:

AN:

1321654

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

643562

show subpopulations

Gnomad4 AFR exome

AF:

0.000892

Gnomad4 AMR exome

AF:

0.0000697

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.55e-7

Gnomad4 OTH exome

AF:

0.0000909

GnomAD4 genome

AF:

0.000197

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.0000551

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.647A>C (p.Q216P) alteration is located in exon 3 (coding exon 3) of the C8orf74 gene. This alteration results from a A to C substitution at nucleotide position 647, causing the glutamine (Q) at amino acid position 216 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

0.18

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.47

M_CAP

Benign

0.035

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.51

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.084

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.010

Polyphen

0.87

Vest4

0.48

MutPred

0.28

Loss of helix (P = 0.0104);

MVP

0.55

MPC

0.094

ClinPred

0.18

GERP RS

5.2

Varity_R

0.68

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over