12-14974207-A-G

Variant names:

• chr12-14974207-A-G
• rs10505784
• NM_006205.3:c.-42+1121A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006205.3(PDE6H):​c.-42+1121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,252 control chromosomes in the GnomAD database, including 1,162 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1162 hom., cov: 33)
• Consequence: PDE6H NM_006205.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.125
• Publications: 7 publications found

Genes affected

PDE6H (HGNC:8790): (phosphodiesterase 6H) This gene encodes the inhibitory (or gamma) subunit of the cone-specific cGMP phosphodiesterase, which is a tetramer composed of two catalytic chains (alpha and beta), and two inhibitory chains (gamma). It is specifically expressed in the retina, and is involved in the transmission and amplification of the visual signal. Mutations in this gene are associated with retinal cone dystrophy type 3A (RCD3A). [provided by RefSeq, Mar 2010]

PDE6H Gene-Disease associations (from GenCC):

• achromatopsia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• retinal cone dystrophy 3A

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6H	NM_006205.3	c.-42+1121A>G		intron_variant	Intron 1 of 3	ENST00000266395.3	NP_006196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6H	ENST00000266395.3	c.-42+1121A>G		intron_variant	Intron 1 of 3	1	NM_006205.3	ENSP00000266395.2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17844 AN: 152132 Hom.: 1161 Cov.: 33

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0939

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.134

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.117 AC: 17845 AN: 152252 Hom.: 1162 Cov.: 33 AF XY: 0.119 AC XY: 8859 AN XY: 74446

African (AFR) AF: 0.0973 AC: 4043 AN: 41554

American (AMR) AF: 0.0938 AC: 1435 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3468

East Asian (EAS) AF: 0.102 AC: 529 AN: 5172

South Asian (SAS) AF: 0.251 AC: 1213 AN: 4824

European-Finnish (FIN) AF: 0.131 AC: 1393 AN: 10600

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7985 AN: 68018

Other (OTH) AF: 0.132 AC: 278 AN: 2114

Alfa AF: 0.122 Hom.: 2293

Bravo AF: 0.111

Asia WGS AF: 0.172 AC: 600 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.2
DANN	Benign	0.52
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10505784; hg19: chr12-15127141;