12-14613281-G-T

Variant names:

• chr12-14613281-G-T
• NM_004963.4:c.3058C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004963.4(GUCY2C):​c.3058C>A​(p.Gln1020Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.3058C>A	p.Gln1020Lys	missense_variant	Exon 27 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.2812C>A	p.Gln938Lys	missense_variant	Exon 27 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1	n.297+355G>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.3058C>A	p.Gln1020Lys	missense_variant	Exon 27 of 27	1	NM_004963.4	ENSP00000261170.3
PLBD1-AS1	ENST00000542401.2	n.848+355G>T		intron_variant	Intron 2 of 4	4
PLBD1-AS1	ENST00000545424.5	n.279+355G>T		intron_variant	Intron 3 of 4	3
PLBD1-AS1	ENST00000660979.1	n.732-5871G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459930 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726450

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.45		Gain of ubiquitination at Q1020 (P = 0.0066);
MVP		0.94
MPC		0.85
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr12-14766215; COSMIC: COSV53788268;