chr10-93663028-G-A

Variant names:

• chr10-93663028-G-A
• rs267606936
• NM_006204.4:c.2368G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_006204.4(PDE6C):​c.2368G>A​(p.Glu790Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDE6C NM_006204.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• cone dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• achromatopsia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-93663028-G-A is Pathogenic according to our data. Variant chr10-93663028-G-A is described in CliVar as Pathogenic. Clinvar id is 8769.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-93663028-G-A is described in CliVar as Pathogenic. Clinvar id is 8769.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6C	NM_006204.4	c.2368G>A	p.Glu790Lys	missense_variant, splice_region_variant	Exon 21 of 22	ENST00000371447.4	NP_006195.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6C	ENST00000371447.4	c.2368G>A	p.Glu790Lys	missense_variant, splice_region_variant	Exon 21 of 22	1	NM_006204.4	ENSP00000360502.3
PDE6C	ENST00000475427.2	n.162+385G>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Achromatopsia 5 Pathogenic:1

Nov 17, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.82
Sift	Benign	0.080	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.91		Gain of MoRF binding (P = 0.0068);
MVP		0.96
MPC		0.97
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.79
Mutation Taster		=84/16	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.64		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267606936; hg19: chr10-95422785;