NM_004963.4:c.1219G>C

Variant names:

• chr12-14669785-C-G
• rs530209992
• NM_004963.4:c.1219G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004963.4(GUCY2C):​c.1219G>C​(p.Val407Leu) 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. 16/22 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. V407M) 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: -0.450
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09691629).

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.1219G>C	p.Val407Leu	missense	Exon 10 of 27	NP_004954.2	P25092
	GUCY2C-AS1	NR_186173.1		n.335+1639C>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.1219G>C	p.Val407Leu	missense	Exon 10 of 27	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.1219G>C	p.Val407Leu	missense	Exon 10 of 28	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.1219G>C	p.Val407Leu	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	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.22
DANN	Benign	0.56
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.45
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.049
Sift	Benign	0.34	T
Sift4G	Benign	0.35	T
Polyphen		0.027	B
Vest4		0.11
MutPred		0.35		Gain of catalytic residue at K403 (P = 0.0362)
MVP		0.48
MPC		0.18
ClinPred		0.045	T
GERP RS		-2.2
Varity_R		0.046
gMVP		0.39
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs530209992; hg19: chr12-14822719;