rs1057520052

Positions:

• chr12-14625847-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004963.4(GUCY2C):​c.2318G>A​(p.Arg773Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.40

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]

C12orf60 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.2318G>A	p.Arg773Gln	missense_variant	21/27	ENST00000261170.5	NP_004954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.2318G>A	p.Arg773Gln	missense_variant	21/27	1	NM_004963.4	ENSP00000261170	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727078

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.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 773 of the GUCY2C protein (p.Arg773Gln). 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. ClinVar contains an entry for this variant (Variation ID: 376780). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 10, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.19
Sift	Benign	0.038	D
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.43		Loss of MoRF binding (P = 0.056);
MVP		0.89
MPC		0.73
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.16
gMVP		0.80

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

Other links and lift over

dbSNP: rs1057520052; hg19: chr12-14778781; COSMIC: COSV53789090;