rs1131978

Variant names:

• chr10-93612977-G-A
• rs1131978
• NM_006204.4:c.252G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-93612977-G-A
• chr10-93612977-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006204.4(PDE6C):​c.252G>A​(p.Leu84Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,613,762 control chromosomes in the GnomAD database, including 26,106 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. L84L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2801 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23305 hom.)
• Consequence: PDE6C NM_006204.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.499
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-93612977-G-A is Benign according to our data. Variant chr10-93612977-G-A is described in ClinVar as Benign. ClinVar VariationId is 95346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.499 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 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.252G>A	p.Leu84Leu	synonymous	Exon 1 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.252G>A	p.Leu84Leu	synonymous	Exon 1 of 22	ENSP00000360502.3	P51160

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28325 AN: 152020 Hom.: 2792 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.180

GnomAD2 exomes AF: 0.162 AC: 40604 AN: 250660 AF XY: 0.164

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.175 AC: 256456 AN: 1461624 Hom.: 23305 Cov.: 34 AF XY: 0.176 AC XY: 127681 AN XY: 727098

African (AFR) AF: 0.239 AC: 7990 AN: 33478

American (AMR) AF: 0.115 AC: 5147 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6548 AN: 26128

East Asian (EAS) AF: 0.0990 AC: 3932 AN: 39698

South Asian (SAS) AF: 0.134 AC: 11540 AN: 86252

European-Finnish (FIN) AF: 0.114 AC: 6081 AN: 53344

Middle Eastern (MID) AF: 0.241 AC: 1384 AN: 5752

European-Non Finnish (NFE) AF: 0.182 AC: 202790 AN: 1111880

Other (OTH) AF: 0.183 AC: 11044 AN: 60382

GnomAD4 genome AF: 0.186 AC: 28367 AN: 152138 Hom.: 2801 Cov.: 32 AF XY: 0.182 AC XY: 13540 AN XY: 74390

African (AFR) AF: 0.233 AC: 9681 AN: 41480

American (AMR) AF: 0.153 AC: 2346 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3468

East Asian (EAS) AF: 0.107 AC: 554 AN: 5158

South Asian (SAS) AF: 0.124 AC: 597 AN: 4826

European-Finnish (FIN) AF: 0.104 AC: 1109 AN: 10616

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12490 AN: 67982

Other (OTH) AF: 0.185 AC: 390 AN: 2112

Alfa AF: 0.130 Hom.: 314

Bravo AF: 0.194

Asia WGS AF: 0.140 AC: 486 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.8
DANN	Benign	0.65
PhyloP100		0.50
PromoterAI		0.0092	Neutral
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: rs1131978; hg19: chr10-95372734; COSMIC: COSV65117966;