6-42173762-C-T

Position:

chr6-42173762-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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).

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:3

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:

GUCA1ANB-GUCA1A (HGNC:):

GUCA1ANB-GUCA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (190/152320) while in subpopulation NFE AF= 0.00204 (139/68036). AF 95% confidence interval is 0.00177. There are 1 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GUCA1A	NM_001384910.1 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	1/4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_001319061.2 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	3/6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_000409.5 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	3/6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319062.2 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	2/5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	1/4	1	NM_001384910.1	ENSP00000362049	P1

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

GnomAD3 exomes

AF:

0.00118

AC:

298

AN:

251478

Hom.:

AF XY:

0.00105

AC XY:

143

AN XY:

135918

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 SAS exome

AF:

0.00

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

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000711

Gnomad4 NFE exome

AF:

0.00178

Gnomad4 OTH exome

AF:

0.00101

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

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00204

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00160

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:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2017	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Cone dystrophy 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

Macular dystrophy

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

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

MutationTaster

Benign

1.0

A;A;A;A

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

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