10-93663161-A-G

Position:

chr10-93663161-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006204.4(PDE6C):c.2501A>G(p.Glu834Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,613,582 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 14 hom. )

Consequence

PDE6C
NM_006204.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.53

Variant links:

Genes affected

PDE6C (HGNC:8787): (phosphodiesterase 6C) This gene encodes the alpha-prime subunit of cone phosphodiesterase, which is composed of a homodimer of two alpha-prime subunits and 3 smaller proteins of 11, 13, and 15 kDa. Mutations in this gene are associated with cone dystrophy type 4 (COD4). [provided by RefSeq, Mar 2010]

PDE6C links:

PDE6C (HGNC:):

PDE6C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009043366).

BP6

Variant 10-93663161-A-G is Benign according to our data. Variant chr10-93663161-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259945.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr10-93663161-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00219 (333/152248) while in subpopulation EAS AF= 0.00425 (22/5172). AF 95% confidence interval is 0.00288. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6C	NM_006204.4 linkuse as main transcript	c.2501A>G	p.Glu834Gly	missense_variant	21/22	ENST00000371447.4	NP_006195.3	P51160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4 linkuse as main transcript	c.2501A>G	p.Glu834Gly	missense_variant	21/22	1	NM_006204.4	ENSP00000360502.3		P51160
PDE6C	ENST00000475427.2 linkuse as main transcript	n.162+518A>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00234

AC:

585

AN:

250486

Hom.:

AF XY:

0.00245

AC XY:

331

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00240

Gnomad SAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00263

GnomAD4 exome

AF:

0.00247

AC:

3607

AN:

1461334

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1829

AN XY:

726942

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.0113

Gnomad4 EAS exome

AF:

0.000807

Gnomad4 SAS exome

AF:

0.00224

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00244

Gnomad4 OTH exome

AF:

0.00409

GnomAD4 genome

AF:

0.00219

AC:

333

AN:

152248

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.00425

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00240

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00228

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00213

AC:

259

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00309

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PDE6C: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Achromatopsia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 01, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cone dystrophy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 01, 2017

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.027

Sift4G

Uncertain

0.041

Polyphen

0.97

Vest4

0.55

MVP

0.81

MPC

0.40

ClinPred

0.033

GERP RS

4.9

Varity_R

0.19

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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