12-14613254-T-G

Variant names:

• chr12-14613254-T-G
• NM_004963.4:c.3085A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004963.4(GUCY2C):​c.3085A>C​(p.Met1029Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 6.49

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.3085A>C	p.Met1029Leu	missense_variant	Exon 27 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.2839A>C	p.Met947Leu	missense_variant	Exon 27 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1	n.297+328T>G		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.3085A>C	p.Met1029Leu	missense_variant	Exon 27 of 27	1	NM_004963.4	ENSP00000261170.3
PLBD1-AS1	ENST00000542401.2	n.848+328T>G		intron_variant	Intron 2 of 4	4
PLBD1-AS1	ENST00000545424.5	n.279+328T>G		intron_variant	Intron 3 of 4	3
PLBD1-AS1	ENST00000660979.1	n.732-5898T>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3085A>C (p.M1029L) alteration is located in exon 27 (coding exon 27) of the GUCY2C gene. This alteration results from a A to C substitution at nucleotide position 3085, causing the methionine (M) at amino acid position 1029 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.53
Sift	Benign	0.14	T
Sift4G	Uncertain	0.027	D
Polyphen		0.97	D
Vest4		0.54
MutPred		0.36		Gain of catalytic residue at I1030 (P = 0.0668);
MVP		0.89
MPC		0.65
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-14766188;