NM_001384910.1:c.296A>G

Variant names:

• chr6-42178374-A-G
• rs104893967
• NM_001384910.1:c.296A>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001384910.1(GUCA1A):​c.296A>G​(p.Tyr99Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000490545: "In vivo functional studies suggest that the Y99C pathogenic variant results in a gain of function of the guanylate cyclase-activating protein, which raises free cGMP levels and elevates cytosolic calcium, resulting in photoreceptor degeneration (Dizhoor et al., 1998" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y99H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.42
• Publications: 47 publications found

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

GUCA1ANB-GUCA1A (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490545: "In vivo functional studies suggest that the Y99C pathogenic variant results in a gain of function of the guanylate cyclase-activating protein, which raises free cGMP levels and elevates cytosolic calcium, resulting in photoreceptor degeneration (Dizhoor et al., 1998; Olshevskaya et al., 2004; Stockman et al., 2014)."; SCV001410587: Experimental studies have shown that this missense change affects GUCA1A function (PMID: 9651312, 9702199).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001384910.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42178373-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1346121.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: 0.22619 (below the threshold of 3.09). GenCC associations: The gene is linked to cone dystrophy, cone dystrophy 3, cone-rod dystrophy, cone-rod dystrophy 14, central areolar choroidal dystrophy, hereditary macular dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 6-42178374-A-G is Pathogenic according to our data. Variant chr6-42178374-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384910.1. 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
	GUCA1A	NM_001384910.1	MANE Select	c.296A>G	p.Tyr99Cys	missense	Exon 2 of 4	NP_001371839.1	P43080
	GUCA1ANB-GUCA1A	NM_000409.5		c.296A>G	p.Tyr99Cys	missense	Exon 4 of 6	NP_000400.2
	GUCA1ANB-GUCA1A	NM_001319061.2		c.296A>G	p.Tyr99Cys	missense	Exon 4 of 6	NP_001305990.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1A	ENST00000372958.2	TSL:1 MANE Select	c.296A>G	p.Tyr99Cys	missense	Exon 2 of 4	ENSP00000362049.1	P43080
	GUCA1ANB-GUCA1A	ENST00000654459.1		c.296A>G	p.Tyr99Cys	missense	Exon 3 of 5	ENSP00000499539.1
	GUCA1A	ENST00000679182.1		c.77A>G	p.Tyr26Cys	missense	Exon 1 of 3	ENSP00000504837.1	A0A7I2V6E2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000516 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cone dystrophy 3 (2)
2	-	-	not provided (2)
1	-	-	Macular dystrophy (1)
1	-	-	Retinal disorder (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Gain of methylation at K97 (P = 0.047)
MVP		0.92
MPC		0.98
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		-0.0050	Neutral
Varity_R		0.89
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs104893967; hg19: chr6-42146112; COSMIC: COSV108025556; COSMIC: COSV108025556;