12-14613166-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004963.4(GUCY2C):​c.3173T>C​(p.Leu1058Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.47
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24807492).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2CNM_004963.4 linkc.3173T>C p.Leu1058Pro missense_variant Exon 27 of 27 ENST00000261170.5 NP_004954.2 P25092
GUCY2CXM_011520631.3 linkc.2927T>C p.Leu976Pro missense_variant Exon 27 of 27 XP_011518933.1
PLBD1-AS1NR_120465.1 linkn.297+240A>G intron_variant Intron 3 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2CENST00000261170.5 linkc.3173T>C p.Leu1058Pro missense_variant Exon 27 of 27 1 NM_004963.4 ENSP00000261170.3 P25092
PLBD1-AS1ENST00000542401.2 linkn.848+240A>G intron_variant Intron 2 of 4 4
PLBD1-AS1ENST00000545424.5 linkn.279+240A>G intron_variant Intron 3 of 4 3
PLBD1-AS1ENST00000660979.1 linkn.732-5986A>G intron_variant Intron 1 of 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461336
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726978
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Sep 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1058 of the GUCY2C protein (p.Leu1058Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. 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 tolerated. 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
0.22
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.092
T
Eigen
Benign
0.031
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.74
T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
0.060
N
REVEL
Benign
0.27
Sift
Benign
0.12
T
Sift4G
Benign
0.11
T
Polyphen
0.078
B
Vest4
0.17
MutPred
0.52
Gain of disorder (P = 0.0089);
MVP
0.87
MPC
0.37
ClinPred
0.70
D
GERP RS
5.8
Varity_R
0.30
gMVP
0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-14766100; API