10-93635607-C-G

Variant names:

• chr10-93635607-C-G
• rs3737228
• NM_006204.4:c.1380C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006204.4(PDE6C):​c.1380C>G​(p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,612,322 control chromosomes in the GnomAD database, including 60,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T460T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4801 hom., cov: 32)
  • Exomes 𝑓: 0.27 (55377 hom.)
• Consequence: PDE6C NM_006204.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.665
• Publications: 14 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 10-93635607-C-G is Benign according to our data. Variant chr10-93635607-C-G is described in ClinVar as Benign. ClinVar VariationId is 259942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.665 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.345 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.1380C>G	p.Thr460Thr	synonymous	Exon 10 of 22	NP_006195.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6C	ENST00000371447.4	TSL:1 MANE Select	c.1380C>G	p.Thr460Thr	synonymous	Exon 10 of 22	ENSP00000360502.3

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36479 AN: 151956 Hom.: 4800 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.251

GnomAD2 exomes AF: 0.274 AC: 68874 AN: 251304 AF XY: 0.270

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.347

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.271 AC: 395991 AN: 1460246 Hom.: 55377 Cov.: 35 AF XY: 0.269 AC XY: 195470 AN XY: 726560

African (AFR) AF: 0.123 AC: 4108 AN: 33462

American (AMR) AF: 0.359 AC: 16057 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7810 AN: 26122

East Asian (EAS) AF: 0.353 AC: 14000 AN: 39668

South Asian (SAS) AF: 0.182 AC: 15727 AN: 86226

European-Finnish (FIN) AF: 0.275 AC: 14693 AN: 53394

Middle Eastern (MID) AF: 0.251 AC: 1448 AN: 5764

European-Non Finnish (NFE) AF: 0.275 AC: 305950 AN: 1110548

Other (OTH) AF: 0.268 AC: 16198 AN: 60352

GnomAD4 genome AF: 0.240 AC: 36490 AN: 152076 Hom.: 4801 Cov.: 32 AF XY: 0.240 AC XY: 17801 AN XY: 74314

African (AFR) AF: 0.133 AC: 5506 AN: 41512

American (AMR) AF: 0.309 AC: 4720 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1033 AN: 3472

East Asian (EAS) AF: 0.359 AC: 1850 AN: 5154

South Asian (SAS) AF: 0.184 AC: 884 AN: 4814

European-Finnish (FIN) AF: 0.277 AC: 2927 AN: 10560

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18766 AN: 67988

Other (OTH) AF: 0.252 AC: 530 AN: 2106

Alfa AF: 0.232 Hom.: 1469

Bravo AF: 0.243

Asia WGS AF: 0.264 AC: 916 AN: 3478

EpiCase AF: 0.284

EpiControl AF: 0.288

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.6
DANN	Benign	0.67
PhyloP100		0.67
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: rs3737228; hg19: chr10-95395364; COSMIC: COSV65115044;