rs616522

Variant names:

• chr10-93635490-A-G
• rs616522
• NM_006204.4:c.1270-7A>G

Variant summary

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

The NM_006204.4(PDE6C):​c.1270-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 1,605,934 control chromosomes in the GnomAD database, including 450,883 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41020 hom., cov: 32)
  • Exomes 𝑓: 0.75 (409863 hom.)
• Consequence: PDE6C NM_006204.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0270
• Publications: 13 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
• PDE6C-related retinopathy

  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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-93635490-A-G is Benign according to our data. Variant chr10-93635490-A-G is described in ClinVar as Benign. ClinVar VariationId is 259940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006204.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6C	NM_006204.4	MANE Select	c.1270-7A>G		splice_region intron	N/A	NP_006195.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6C	ENST00000371447.4	TSL:1 MANE Select	c.1270-7A>G		splice_region intron	N/A	ENSP00000360502.3	P51160

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111462 AN: 151890 Hom.: 40982 Cov.: 32

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.743

GnomAD2 exomes AF: 0.733 AC: 184050 AN: 251112 AF XY: 0.741

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.643

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.727

Gnomad NFE exome AF: 0.749

Gnomad OTH exome AF: 0.767

GnomAD4 exome AF: 0.750 AC: 1089779 AN: 1453926 Hom.: 409863 Cov.: 31 AF XY: 0.752 AC XY: 544550 AN XY: 723928

African (AFR) AF: 0.720 AC: 24010 AN: 33362

American (AMR) AF: 0.651 AC: 29085 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 19053 AN: 26068

East Asian (EAS) AF: 0.656 AC: 25985 AN: 39628

South Asian (SAS) AF: 0.828 AC: 71218 AN: 86054

European-Finnish (FIN) AF: 0.731 AC: 39008 AN: 53360

Middle Eastern (MID) AF: 0.773 AC: 4442 AN: 5744

European-Non Finnish (NFE) AF: 0.753 AC: 832142 AN: 1104882

Other (OTH) AF: 0.746 AC: 44836 AN: 60130

GnomAD4 genome AF: 0.734 AC: 111558 AN: 152008 Hom.: 41020 Cov.: 32 AF XY: 0.735 AC XY: 54635 AN XY: 74290

African (AFR) AF: 0.715 AC: 29623 AN: 41452

American (AMR) AF: 0.704 AC: 10738 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2566 AN: 3472

East Asian (EAS) AF: 0.650 AC: 3361 AN: 5174

South Asian (SAS) AF: 0.827 AC: 3985 AN: 4816

European-Finnish (FIN) AF: 0.728 AC: 7677 AN: 10544

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.752 AC: 51097 AN: 67978

Other (OTH) AF: 0.742 AC: 1568 AN: 2112

Alfa AF: 0.745 Hom.: 189697

Bravo AF: 0.726

Asia WGS AF: 0.736 AC: 2558 AN: 3476

EpiCase AF: 0.747

EpiControl AF: 0.745

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Cone dystrophy 4 (2)
-	-	1	Achromatopsia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-0.027
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0
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: rs616522; hg19: chr10-95395247; COSMIC: COSV65118225;