Genetic Variant GUCA1C:p.Ile168Met (chr3-108908148-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005459.4(GUCA1C):c.504T>G(p.Ile168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

GUCA1C
NM_005459.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0510

Variant links:

Genes affected

GUCA1C (HGNC:4680): (guanylate cyclase activator 1C) Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in signal transduction. Predicted to be located in photoreceptor disc membrane. [provided by Alliance of Genome Resources, Apr 2022]

GUCA1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059412986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1C	NM_005459.4 link	c.504T>G	p.Ile168Met	missense_variant	Exon 4 of 4	ENST00000261047.8	NP_005450.3	O95843-1
GUCA1C	NM_001363884.1 link	c.544T>G	p.Cys182Gly	missense_variant	Exon 4 of 4		NP_001350813.1
GUCA1C	XM_011513334.3 link	c.252T>G	p.Ile84Met	missense_variant	Exon 4 of 4		XP_011511636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1C	ENST00000261047.8 link	c.504T>G	p.Ile168Met	missense_variant	Exon 4 of 4	1	NM_005459.4	ENSP00000261047.3		O95843-1
GUCA1C	ENST00000393963.7 link	c.544T>G	p.Cys182Gly	missense_variant	Exon 4 of 4	1		ENSP00000377535.3		C9JNI2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251334

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.504T>G (p.I168M) alteration is located in exon 4 (coding exon 4) of the GUCA1C gene. This alteration results from a T to G substitution at nucleotide position 504, causing the isoleucine (I) at amino acid position 168 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.5

DANN

Benign

0.067

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.24

M_CAP

Benign

0.0077

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.30

REVEL

Benign

0.089

Sift

Benign

0.12

Sift4G

Benign

0.67

Polyphen

0.0030

Vest4

0.25

MutPred

0.55

Loss of helix (P = 3e-04);

MVP

0.20

ClinPred

0.025

GERP RS

-1.4

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