NM_004963.4:c.3035C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_004963.4(GUCY2C):c.3035C>A(p.Thr1012Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000757 in 1,585,262 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1012I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

GUCY2C
NM_004963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.40

Publications

4 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26164836).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000131 (2/152262) while in subpopulation SAS AF = 0.000414 (2/4830). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4 link	c.3035C>A	p.Thr1012Asn	missense_variant	Exon 26 of 27	ENST00000261170.5	NP_004954.2	P25092
GUCY2C	XM_011520631.3 link	c.2789C>A	p.Thr930Asn	missense_variant	Exon 26 of 27		XP_011518933.1
PLBD1-AS1	NR_120465.1 link	n.346+309G>T		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GUCY2C	ENST00000261170.5 link	c.3035C>A	p.Thr1012Asn	missense_variant	Exon 26 of 27	1	NM_004963.4	ENSP00000261170.3	P25092
PLBD1-AS1	ENST00000542401.2 link	n.897+309G>T		intron_variant	Intron 3 of 4	4
PLBD1-AS1	ENST00000545424.5 link	n.328+309G>T		intron_variant	Intron 4 of 4	3
PLBD1-AS1	ENST00000660979.1 link	n.732-4273G>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000884

AC:

AN:

226266

AF XY:

0.00000812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000629

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000698

AC:

AN:

1433000

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

713222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31768

American (AMR)

AF:

0.00

AC:

AN:

39386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

37738

South Asian (SAS)

AF:

0.0000970

AC:

AN:

82514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1098208

Other (OTH)

AF:

0.0000169

AC:

AN:

59262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1012 of the GUCY2C protein (p.Thr1012Asn). This variant is present in population databases (rs535349983, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1991186). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.26

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.6

PhyloP100

4.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.4

REVEL

Uncertain

0.42

Sift

Uncertain

0.0050

Sift4G

Benign

0.061

Polyphen

0.72

Vest4

0.38

MutPred

0.29

Gain of catalytic residue at P1013 (P = 2e-04);

MVP

0.86

MPC

0.44

ClinPred

0.62

GERP RS

5.2

Varity_R

0.17

gMVP

0.37

Mutation Taster

=61/39

polymorphism

(source)

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

Publications

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NM_004963.4:c.3035C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over