6-42173698-T-C

Position:

chr6-42173698-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2

The NM_001384910.1(GUCA1A):c.85T>C(p.Cys29Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,852 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

GUCA1A
NM_001384910.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

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 Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000328 (5/152292) while in subpopulation AFR AF= 0.00012 (5/41564). AF 95% confidence interval is 0.0000473. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GUCA1A	NM_001384910.1 linkuse as main transcript	c.85T>C	p.Cys29Arg	missense_variant	1/4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_001319061.2 linkuse as main transcript	c.85T>C	p.Cys29Arg	missense_variant	3/6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_000409.5 linkuse as main transcript	c.85T>C	p.Cys29Arg	missense_variant	3/6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319062.2 linkuse as main transcript	c.85T>C	p.Cys29Arg	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.85T>C	p.Cys29Arg	missense_variant	1/4	1	NM_001384910.1	ENSP00000362049	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251488

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with GUCA1A-related conditions. This variant is present in population databases (rs199885693, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 29 of the GUCA1A protein (p.Cys29Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;.;D;D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;D;.;.;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.8

.;.;H;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-10

D;.;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

.;.;D;D;D

Vest4

0.73, 0.80, 0.84, 0.83

MVP

0.91

MPC

1.2

ClinPred

1.0

GERP RS

5.8

Varity_R

0.95

gMVP

0.84

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