Variant chr12-14669728-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004963.4(GUCY2C):c.1276G>T(p.Gly426Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,361,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.958

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 links:

GUCY2C-AS1 (HGNC:56054): (GUCY2C antisense RNA 1)

GUCY2C-AS1 links:

C12orf60 (HGNC:):

C12orf60 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2C	NM_004963.4 linkuse as main transcript	c.1276G>T	p.Gly426Cys	missense_variant	10/27	ENST00000261170.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2C	ENST00000261170.5 linkuse as main transcript	c.1276G>T	p.Gly426Cys	missense_variant	10/27	1	NM_004963.4	P1
GUCY2C-AS1	ENST00000501178.2 linkuse as main transcript	n.199-2538C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

240892

Hom.:

AF XY:

0.0000384

AC XY:

AN XY:

130320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000286

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000661

AC:

AN:

1361114

Hom.:

Cov.:

AF XY:

0.00000732

AC XY:

AN XY:

682710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000212

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1365619). This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. This variant is present in population databases (rs757682446, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 426 of the GUCY2C protein (p.Gly426Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.048

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.44

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.31

Sift

Benign

0.060

Sift4G

Uncertain

0.050

Polyphen

0.98

Vest4

0.40

MutPred

0.54

Gain of catalytic residue at R427 (P = 8e-04);

MVP

0.89

MPC

0.60

ClinPred

0.30

GERP RS

2.6

Varity_R

0.11

gMVP

0.49

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