Genetic Variant NM_004963.4:c.2782T>G (chr12-14619304-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_004963.4(GUCY2C):c.2782T>G(p.Cys928Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C928R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.25

Variant links:

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 links:

PLBD1-AS1 (HGNC:51143): (PLBD1 antisense RNA 1)

PLBD1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-14619304-A-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4 link	c.2782T>G	p.Cys928Gly	missense_variant	Exon 24 of 27	ENST00000261170.5	NP_004954.2	P25092
GUCY2C	XM_011520631.3 link	c.2536T>G	p.Cys846Gly	missense_variant	Exon 24 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1 link	n.499A>C		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GUCY2C	ENST00000261170.5 link	c.2782T>G	p.Cys928Gly	missense_variant	Exon 24 of 27	1	NM_004963.4	ENSP00000261170.3	P25092
PLBD1-AS1	ENST00000542401.2 link	n.1050A>C		non_coding_transcript_exon_variant	Exon 4 of 5	4
PLBD1-AS1	ENST00000660979.1 link	n.884A>C		non_coding_transcript_exon_variant	Exon 2 of 4
PLBD1-AS1	ENST00000545424.5 link	n.*6A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452670

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-9.3

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.045

Polyphen

1.0

Vest4

0.83

MutPred

0.74

Gain of catalytic residue at G926 (P = 0);

MVP

0.97

MPC

0.83

ClinPred

1.0

GERP RS

5.3

Varity_R

0.90

gMVP

0.95

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over