chr12-14669806-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004963.4(GUCY2C):​c.1198C>G​(p.His400Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)

Consequence

GUCY2C
NM_004963.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51
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]
GUCY2C-AS1 (HGNC:56054): (GUCY2C antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40932262).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GUCY2CNM_004963.4 linkuse as main transcriptc.1198C>G p.His400Asp missense_variant 10/27 ENST00000261170.5 NP_004954.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GUCY2CENST00000261170.5 linkuse as main transcriptc.1198C>G p.His400Asp missense_variant 10/271 NM_004963.4 ENSP00000261170 P1
GUCY2C-AS1ENST00000501178.2 linkuse as main transcriptn.199-2460G>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
25
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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2023Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GUCY2C protein function. This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 400 of the GUCY2C protein (p.His400Asp). 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
0.21
BayesDel_addAF
Benign
-0.018
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
17
DANN
Benign
0.77
DEOGEN2
Benign
0.14
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.41
T
MetaSVM
Benign
-0.83
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
0.78
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.88
N
REVEL
Benign
0.19
Sift
Benign
0.59
T
Sift4G
Benign
0.58
T
Polyphen
0.045
B
Vest4
0.53
MutPred
0.43
Gain of catalytic residue at V401 (P = 0.0014);
MVP
0.76
MPC
0.27
ClinPred
0.18
T
GERP RS
4.6
Varity_R
0.15
gMVP
0.64

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: chr12-14822740; API