12-14669802-A-G

Variant names:

• chr12-14669802-A-G
• NM_004963.4:c.1202T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004963.4(GUCY2C):​c.1202T>C​(p.Val401Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V401I) has been classified 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: -2.77
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06391275).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	NM_004963.4	MANE Select	c.1202T>C	p.Val401Ala	missense	Exon 10 of 27	NP_004954.2	P25092
	GUCY2C-AS1	NR_186173.1		n.335+1656A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	ENST00000261170.5	TSL:1 MANE Select	c.1202T>C	p.Val401Ala	missense	Exon 10 of 27	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.1202T>C	p.Val401Ala	missense	Exon 10 of 28	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.1202T>C	p.Val401Ala	missense	Exon 10 of 26	ENSP00000640842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0060
DANN	Benign	0.27
DEOGEN2	Benign	0.084	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.047
Sift	Benign	0.77	T
Sift4G	Benign	0.76	T
Polyphen		0.0020	B
Vest4		0.16
MutPred		0.38		Gain of catalytic residue at D398 (P = 6e-04)
MVP		0.41
MPC		0.22
ClinPred		0.029	T
GERP RS		-9.2
Varity_R		0.017
gMVP		0.47
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr12-14822736;