12-14613238-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_004963.4(GUCY2C):​c.3101T>C​(p.Leu1034Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,268 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 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.55

Publications

2 publications found
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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2CNM_004963.4 linkc.3101T>C p.Leu1034Ser missense_variant Exon 27 of 27 ENST00000261170.5 NP_004954.2 P25092
GUCY2CXM_011520631.3 linkc.2855T>C p.Leu952Ser missense_variant Exon 27 of 27 XP_011518933.1
PLBD1-AS1NR_120465.1 linkn.297+312A>G intron_variant Intron 3 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2CENST00000261170.5 linkc.3101T>C p.Leu1034Ser missense_variant Exon 27 of 27 1 NM_004963.4 ENSP00000261170.3 P25092

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152060
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000797
AC:
2
AN:
251036
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1461208
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
726938
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33436
American (AMR)
AF:
0.0000224
AC:
1
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86240
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1111500
Other (OTH)
AF:
0.0000828
AC:
5
AN:
60352
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152060
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74266
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41428
American (AMR)
AF:
0.0000656
AC:
1
AN:
15234
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
67992
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.558
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 02, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3101T>C (p.L1034S) alteration is located in exon 27 (coding exon 27) of the GUCY2C gene. This alteration results from a T to C substitution at nucleotide position 3101, causing the leucine (L) at amino acid position 1034 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Jul 17, 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 serine, which is neutral and polar, at codon 1034 of the GUCY2C protein (p.Leu1034Ser). This variant is present in population databases (rs746455153, gnomAD 0.003%). 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 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
Uncertain
0.39
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.75
T
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.55
D
MutationAssessor
Uncertain
2.6
M
PhyloP100
7.6
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.2
D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.68
MutPred
0.46
Loss of helix (P = 0.0017);
MVP
0.96
MPC
0.89
ClinPred
0.98
D
GERP RS
5.8
Varity_R
0.64
gMVP
0.70
Mutation Taster
=64/36
polymorphism

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

Other links and lift over

dbSNP: rs746455153; hg19: chr12-14766172; API