chr12-14973069-G-C

Variant names:

• chr12-14973069-G-C
• rs11056264
• NM_006205.3:c.-59G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006205.3(PDE6H):​c.-59G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,166 control chromosomes in the GnomAD database, including 1,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1167 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE6H NM_006205.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.125
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-14973069-G-C is Benign according to our data. Variant chr12-14973069-G-C is described in ClinVar as Benign. ClinVar VariationId is 307780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.-59G>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000266395.3	NP_006196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6H	ENST00000266395.3	c.-59G>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_006205.3	ENSP00000266395.2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17920 AN: 152048 Hom.: 1166 Cov.: 32

Gnomad AFR AF: 0.0999

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.134

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.118 AC: 17921 AN: 152166 Hom.: 1167 Cov.: 32 AF XY: 0.119 AC XY: 8882 AN XY: 74376

African (AFR) AF: 0.0997 AC: 4142 AN: 41524

American (AMR) AF: 0.0936 AC: 1432 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 734 AN: 3466

East Asian (EAS) AF: 0.101 AC: 523 AN: 5162

South Asian (SAS) AF: 0.252 AC: 1211 AN: 4814

European-Finnish (FIN) AF: 0.131 AC: 1386 AN: 10590

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

European-Non Finnish (NFE) AF: 0.117 AC: 7980 AN: 68002

Other (OTH) AF: 0.131 AC: 277 AN: 2110

Alfa AF: 0.0594 Hom.: 63

Bravo AF: 0.112

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal cone dystrophy 3A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.56
PhyloP100		0.13
PromoterAI		0.043	Neutral
Mutation Taster		=300/0	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: rs11056264; hg19: chr12-15126003;