6-42173762-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_001384910.1(GUCA1A):c.149C>T(p.Pro50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 0 hom. )

Consequence

GUCA1A
NM_001384910.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:4

Conservation

PhyloP100: 2.64

Variant links:

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]

GUCA1A links:

ENSG00000290147 (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]

ENSG00000290147 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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 3, cone-rod dystrophy, cone dystrophy, central areolar choroidal dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.029534549).

BS2

High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 1 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 3 of 6		NP_000400.2	P43080
GUCA1ANB-GUCA1A	NM_001319061.2 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 3 of 6		NP_001305990.1	P43080
GUCA1ANB-GUCA1A	NM_001319062.2 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 2 of 5		NP_001305991.1	P43080B2R9P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 1 of 4	1	NM_001384910.1	ENSP00000362049.1		P43080
ENSG00000290147	ENST00000654459.1 link	c.149C>T	p.Pro50Leu	missense_variant	Exon 2 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00204

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00118

AC:

298

AN:

251478

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00150

AC:

2199

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1013

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.00203

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.000115

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000504

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000464

AC:

AN:

86254

Gnomad4 FIN exome

AF:

0.000711

AC:

AN:

53416

Gnomad4 NFE exome

AF:

0.00178

AC:

1984

AN:

1111978

Gnomad4 Remaining exome

AF:

0.00101

AC:

AN:

60388

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152320

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000577

AC:

0.000577478

AN:

0.000577478

Gnomad4 AMR

AF:

0.00118

AC:

0.00117678

AN:

0.00117678

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000377

AC:

0.000376506

AN:

0.000376506

Gnomad4 NFE

AF:

0.00204

AC:

0.00204304

AN:

0.00204304

Gnomad4 OTH

AF:

0.00189

AC:

0.00189036

AN:

0.00189036

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00103

AC:

125

EpiCase

AF:

0.00180

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 03, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The P50L variant in the GUCA1A gene has been reported previously in three members of a family with variable ocular abnormalities, ranging from minimal macular involvement to moderately severe cone-rod dystrophy (Downes et al., 2001). The P50L variant was also identified in a patient with cone and cone-rod dystrophy, however, informative familial segregation data was not included to confirm if this variant occurred de novo or was inherited in this individual (Boulanger-Scemama et al., 2015). The NHLBI ESP Exome Sequencing Project reports P50L was observed in 0.12% (10/8600) alleles from individuals of European American ancestry, indicating it may be a rare (benign) variant in this population. The P50L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. One in vitro functional study concluded that this variant results in impaired calcium binding, however, enzyme assays showed similar results for the P50L variant compared to wild type enzyme, and it is unclear how this variant impacts the protein function (Sokal et al., 2000). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We now interpret P50L as a variant of uncertain significance. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone dystrophy 3

Pathogenic:1Benign:1

Mar 21, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Usher syndrome

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Macular dystrophy

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

.;.;D;D;D

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

.;T;.;.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.030

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.9

.;.;L;L;L

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.0

D;.;D;D;D

REVEL

Uncertain

0.44

Sift

Benign

0.13

T;.;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.13

.;.;B;B;B

Vest4

0.37, 0.16, 0.15, 0.16

MVP

0.83

MPC

0.25

ClinPred

0.030

GERP RS

5.8

Varity_R

0.21

gMVP

0.56

Mutation Taster

=77/23

polymorphism

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over