12-14613194-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_004963.4(GUCY2C):​c.3145C>T​(p.Arg1049Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,090 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 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.39
Variant links:
Genes affected
GUCY2C (HGNC:4688): (guanylate cyclase 2C) This gene encodes a transmembrane protein that functions as a receptor for endogenous peptides guanylin and uroguanylin, and the heat-stable E. coli enterotoxin. The encoded protein activates the cystic fibrosis transmembrane conductance regulator. Mutations in this gene are associated with familial diarrhea (autosomal dominant) and meconium ileus (autosomal recessive). [provided by RefSeq, Nov 2016]
PLBD1-AS1 (HGNC:51143): (PLBD1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.745
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000658 (10/152072) while in subpopulation NFE AF= 0.000103 (7/68008). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2CNM_004963.4 linkc.3145C>T p.Arg1049Trp missense_variant Exon 27 of 27 ENST00000261170.5 NP_004954.2 P25092
GUCY2CXM_011520631.3 linkc.2899C>T p.Arg967Trp missense_variant Exon 27 of 27 XP_011518933.1
PLBD1-AS1NR_120465.1 linkn.297+268G>A intron_variant Intron 3 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2CENST00000261170.5 linkc.3145C>T p.Arg1049Trp missense_variant Exon 27 of 27 1 NM_004963.4 ENSP00000261170.3 P25092
PLBD1-AS1ENST00000542401.2 linkn.848+268G>A intron_variant Intron 2 of 4 4
PLBD1-AS1ENST00000545424.5 linkn.279+268G>A intron_variant Intron 3 of 4 3
PLBD1-AS1ENST00000660979.1 linkn.732-5958G>A intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152072
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000717
AC:
18
AN:
251212
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000130
AC:
190
AN:
1461018
Hom.:
0
Cov.:
30
AF XY:
0.000120
AC XY:
87
AN XY:
726838
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000161
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000658
AC:
10
AN:
152072
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.000136
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000491
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Dec 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1049 of the GUCY2C protein (p.Arg1049Trp). This variant is present in population databases (rs140551603, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1520722). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.083
T
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.81
T
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.74
D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Uncertain
2.5
M
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-2.5
N
REVEL
Uncertain
0.38
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.50
MVP
0.91
MPC
0.67
ClinPred
0.40
T
GERP RS
5.8
Varity_R
0.12
gMVP
0.60

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.

Other links and lift over

dbSNP: rs140551603; hg19: chr12-14766128; COSMIC: COSV53787421; API