chr12-14669728-C-A

Variant names:

• chr12-14669728-C-A
• rs757682446
• NM_004963.4:c.1276G>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.958

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 Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000661 (9/1361114) while in subpopulation AMR AF= 0.000212 (9/42364). AF 95% confidence interval is 0.000111. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 20. 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.1276G>T	p.Gly426Cys	missense_variant	Exon 10 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.1030G>T	p.Gly344Cys	missense_variant	Exon 10 of 27		XP_011518933.1
GUCY2C-AS1	NR_186173.1	n.335+1582C>A		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.1276G>T	p.Gly426Cys	missense_variant	Exon 10 of 27	1	NM_004963.4	ENSP00000261170.3
GUCY2C-AS1	ENST00000501178.2	n.199-2538C>A		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000374 AC: 9 AN: 240892 Hom.: 0 AF XY: 0.0000384 AC XY: 5 AN XY: 130320

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: 9 AN: 1361114 Hom.: 0 Cov.: 20 AF XY: 0.00000732 AC XY: 5 AN XY: 682710

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.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.31
Sift	Benign	0.060	T
Sift4G	Uncertain	0.050	T
Polyphen		0.98	D
Vest4		0.40
MutPred		0.54		Gain of catalytic residue at R427 (P = 8e-04);
MVP		0.89
MPC		0.60
ClinPred		0.30	T
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

Other links and lift over

dbSNP: rs757682446; hg19: chr12-14822662;