12-14669736-T-A

Variant names:

• chr12-14669736-T-A
• rs748939303
• NM_004963.4:c.1268A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_004963.4(GUCY2C):​c.1268A>T​(p.Asp423Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000853 in 1,406,998 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000853 (12/1406998) while in subpopulation AMR AF= 0.000278 (12/43180). AF 95% confidence interval is 0.00016. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.1268A>T	p.Asp423Val	missense_variant	Exon 10 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.1022A>T	p.Asp341Val	missense_variant	Exon 10 of 27		XP_011518933.1
GUCY2C-AS1	NR_186173.1	n.335+1590T>A		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.1268A>T	p.Asp423Val	missense_variant	Exon 10 of 27	1	NM_004963.4	ENSP00000261170.3
GUCY2C-AS1	ENST00000501178.2	n.199-2530T>A		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000409 AC: 10 AN: 244328 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000309

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: 0.00000853 AC: 12 AN: 1406998 Hom.: 0 Cov.: 23 AF XY: 0.00000284 AC XY: 2 AN XY: 703086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000278

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.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 423 of the GUCY2C protein (p.Asp423Val). This variant is present in population databases (rs748939303, gnomAD 0.03%). 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: 2066764). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2C protein function. 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	Pathogenic	0.79
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.96	P
Vest4		0.59
MutPred		0.61		Gain of catalytic residue at K419 (P = 0);
MVP		0.90
MPC		0.82
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs748939303; hg19: chr12-14822670;