rs148661165

chr10-93663161-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 8.53

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]

ACMG classification

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: {Uncertain_significance=2, Likely_benign=3}. 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 GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6C	NM_006204.4	c.2501A>G	p.Glu834Gly	missense_variant	21/22	ENST00000371447.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6C	ENST00000371447.4	c.2501A>G	p.Glu834Gly	missense_variant	21/22	1	NM_006204.4	P1
PDE6C	ENST00000475427.2	n.162+518A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152130 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00245 AC XY: 331 AN XY: 135342

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.: 14 Cov.: 32 AF XY: 0.00252 AC XY: 1829 AN XY: 726942

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.: 0 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74446

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.: 1

Bravo AF: 0.00228

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00309

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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

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

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.49	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.041	D
Polyphen		0.97	D
Vest4		0.55
MVP		0.81
MPC		0.40
ClinPred		0.033	T
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

Other links and lift over

dbSNP: rs148661165; hg19: chr10-95422918;