8-10698002-A-C

Position:

chr8-10698002-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040032.2(C8orf74):c.645A>C(p.Arg215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000873 in 1,478,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

C8orf74
NM_001040032.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.633

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11067322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8orf74	NM_001040032.2 linkuse as main transcript	c.645A>C	p.Arg215Ser	missense_variant	3/4	ENST00000304519.10
C8orf74	XM_047421493.1 linkuse as main transcript	c.702A>C	p.Arg234Ser	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
C8orf74	ENST00000304519.10 linkuse as main transcript	c.645A>C	p.Arg215Ser	missense_variant	3/4	1	NM_001040032.2	P1
C8orf74	ENST00000523289.5 linkuse as main transcript	c.*537A>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	2
RP1L1	ENST00000329335.3 linkuse as main transcript	n.231+13955T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000329

AC:

AN:

91080

Hom.:

AF XY:

0.0000420

AC XY:

AN XY:

47654

show subpopulations

Gnomad AFR exome

AF:

0.000297

Gnomad AMR exome

AF:

0.0000558

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:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1326006

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

646034

show subpopulations

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.000101

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:

0.00

Gnomad4 OTH exome

AF:

0.0000906

GnomAD4 genome

AF:

0.000479

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000392

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:

0.000569

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.000812

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000100

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

Sep 14, 2021

The c.645A>C (p.R215S) 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 645, causing the arginine (R) at amino acid position 215 to be replaced by a serine (S). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.098

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.48

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.92

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.090

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.44

MutPred

0.38

Gain of phosphorylation at R215 (P = 0.0709);

MVP

0.43

MPC

0.049

ClinPred

0.38

GERP RS

-0.27

Varity_R

0.19

gMVP

0.54

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

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