12-14669803-C-T

Position:

chr12-14669803-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004963.4(GUCY2C):c.1201G>A(p.Val401Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,594,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012611568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2C	NM_004963.4 linkuse as main transcript	c.1201G>A	p.Val401Ile	missense_variant	10/27	ENST00000261170.5	NP_004954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5 linkuse as main transcript	c.1201G>A	p.Val401Ile	missense_variant	10/27	1	NM_004963.4	ENSP00000261170	P1
GUCY2C-AS1	ENST00000501178.2 linkuse as main transcript	n.199-2463C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000147

AC:

AN:

245112

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

132476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000805

Gnomad EAS exome

AF:

0.00134

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.0000901

AC:

130

AN:

1442310

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

718432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00135

Gnomad4 EAS exome

AF:

0.00161

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000182

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.000105

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000964

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000888

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.1201G>A (p.V401I) alteration is located in exon 10 (coding exon 10) of the GUCY2C gene. This alteration results from a G to A substitution at nucleotide position 1201, causing the valine (V) at amino acid position 401 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 401 of the GUCY2C protein (p.Val401Ile). This variant is present in population databases (rs201126623, gnomAD 0.1%). 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: 1008461). Advanced 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 with a negative predictive value of 80%. 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

0.067

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.0070

DANN

Benign

0.58

DEOGEN2

Benign

0.10

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.24

M_CAP

Benign

0.027

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.11

REVEL

Benign

0.074

Sift

Benign

0.21

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.072

MVP

0.50

MPC

0.15

ClinPred

0.019

GERP RS

-9.2

Varity_R

0.029

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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