12-14619304-A-G

Variant names:

• chr12-14619304-A-G
• rs587784573
• NM_004963.4:c.2782T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004963.4(GUCY2C):​c.2782T>C​(p.Cys928Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 12-14619304-A-G is Pathogenic according to our data. Variant chr12-14619304-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 161159.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-14619304-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.2782T>C	p.Cys928Arg	missense_variant	Exon 24 of 27	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.2536T>C	p.Cys846Arg	missense_variant	Exon 24 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1	n.499A>G		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5	c.2782T>C	p.Cys928Arg	missense_variant	Exon 24 of 27	1	NM_004963.4	ENSP00000261170.3
PLBD1-AS1	ENST00000542401.2	n.1050A>G		non_coding_transcript_exon_variant	Exon 4 of 5	4
PLBD1-AS1	ENST00000660979.1	n.884A>G		non_coding_transcript_exon_variant	Exon 2 of 4
PLBD1-AS1	ENST00000545424.5	n.*6A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452670 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 723344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Meconium ileus Pathogenic:1

Aug 13, 2014

FORGE Canada, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.79		Gain of catalytic residue at V933 (P = 0);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs587784573; hg19: chr12-14772238;