rs701865

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_006204.4(PDE6C):c.808T>A(p.Ser270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,612,712 control chromosomes in the GnomAD database, including 109,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11989 hom., cov: 32)

Exomes 𝑓: 0.36 ( 97353 hom. )

Consequence

PDE6C
NM_006204.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain GAF 2 (size 177) in uniprot entity PDE6C_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_006204.4

BP4

Computational evidence support a benign effect (MetaRNN=6.941855E-4).

BP6

Variant 10-93622016-T-A is Benign according to our data. Variant chr10-93622016-T-A is described in ClinVar as [Benign]. Clinvar id is 259947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-93622016-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6C	NM_006204.4 linkuse as main transcript	c.808T>A	p.Ser270Thr	missense_variant	4/22	ENST00000371447.4	NP_006195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4 linkuse as main transcript	c.808T>A	p.Ser270Thr	missense_variant	4/22	1	NM_006204.4	ENSP00000360502	P1

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59675

AN:

151866

Hom.:

11968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.462

Gnomad AMI

AF:

0.432

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.353

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.379

GnomAD3 exomes

AF:

0.376

AC:

94516

AN:

251358

Hom.:

18334

AF XY:

0.369

AC XY:

50155

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.468

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.473

Gnomad SAS exome

AF:

0.318

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.362

AC:

529034

AN:

1460726

Hom.:

97353

Cov.:

AF XY:

0.361

AC XY:

262270

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.464

Gnomad4 AMR exome

AF:

0.435

Gnomad4 ASJ exome

AF:

0.342

Gnomad4 EAS exome

AF:

0.479

Gnomad4 SAS exome

AF:

0.321

Gnomad4 FIN exome

AF:

0.335

Gnomad4 NFE exome

AF:

0.356

Gnomad4 OTH exome

AF:

0.377

GnomAD4 genome

AF:

0.393

AC:

59741

AN:

151986

Hom.:

11989

Cov.:

AF XY:

0.390

AC XY:

28986

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.462

Gnomad4 AMR

AF:

0.420

Gnomad4 ASJ

AF:

0.337

Gnomad4 EAS

AF:

0.478

Gnomad4 SAS

AF:

0.316

Gnomad4 FIN

AF:

0.329

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.382

Alfa

AF:

0.345

Hom.:

6946

Bravo

AF:

0.408

TwinsUK

AF:

0.375

AC:

1390

ALSPAC

AF:

0.362

AC:

1397

ESP6500AA

AF:

0.463

AC:

2039

ESP6500EA

AF:

0.355

AC:

3050

ExAC

AF:

0.373

AC:

45271

Asia WGS

AF:

0.417

AC:

1449

AN:

3478

EpiCase

AF:

0.363

EpiControl

AF:

0.366

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22449891) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone dystrophy 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Achromatopsia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.2

DANN

Benign

0.88

DEOGEN2

Benign

0.076

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.23

MetaRNN

Benign

0.00069

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.030

REVEL

Benign

0.092

Sift

Benign

0.45

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.014

MPC

0.23

ClinPred

0.0040

GERP RS

4.8

Varity_R

0.036

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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