12-14613250-A-G

Variant names:

• chr12-14613250-A-G
• NM_004963.4:c.3089T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004963.4(GUCY2C):​c.3089T>C​(p.Ile1030Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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)

ACMG classification

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=0.41818747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.3089T>C	p.Ile1030Thr	missense_variant	Exon 27 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.2843T>C	p.Ile948Thr	missense_variant	Exon 27 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1	n.297+324A>G		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.3089T>C	p.Ile1030Thr	missense_variant	Exon 27 of 27	1	NM_004963.4	ENSP00000261170.3
PLBD1-AS1	ENST00000542401.2	n.848+324A>G		intron_variant	Intron 2 of 4	4
PLBD1-AS1	ENST00000545424.5	n.279+324A>G		intron_variant	Intron 3 of 4	3
PLBD1-AS1	ENST00000660979.1	n.732-5902A>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1030 of the GUCY2C protein (p.Ile1030Thr). 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. 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 tolerated. 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	0.48
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.033	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.51	P
Vest4		0.33
MutPred		0.50		Loss of stability (P = 0.0055);
MVP		0.89
MPC		0.33
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.54

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: chr12-14766184;