NM_004963.4:c.1160A>G

Variant names:

• chr12-14672883-T-C
• rs587776905
• NM_004963.4:c.1160A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_004963.4(GUCY2C):​c.1160A>G​(p.Asp387Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D387E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.57
• Publications: 13 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-14672883-T-C is Pathogenic according to our data. Variant chr12-14672883-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 31604.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1160A>G	p.Asp387Gly	missense	Exon 9 of 27	NP_004954.2	P25092
	GUCY2C-AS1	NR_186173.1		n.384+569T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	ENST00000261170.5	TSL:1 MANE Select	c.1160A>G	p.Asp387Gly	missense	Exon 9 of 27	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.1160A>G	p.Asp387Gly	missense	Exon 9 of 28	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.1160A>G	p.Asp387Gly	missense	Exon 9 of 26	ENSP00000640842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250378 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439322 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 717466

African (AFR) AF: 0.00 AC: 0 AN: 32998

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 85600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091890

Other (OTH) AF: 0.0000168 AC: 1 AN: 59640

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meconium ileus (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.39
MutPred		0.45		Gain of catalytic residue at S385 (P = 0.001)
MVP		0.76
MPC		0.25
ClinPred		0.072	T
GERP RS		3.9
Varity_R		0.070
gMVP		0.54
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776905; hg19: chr12-14825817;