12-14628744-GA-GAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004963.4(GUCY2C):c.2158-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20634 hom., cov: 0)

Exomes 𝑓: 0.41 ( 83127 hom. )

Consequence

GUCY2C
NM_004963.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.995

Publications

6 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 Gene-Disease associations (from GenCC):

congenital diarrhea 6
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
congenital sodium diarrhea
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GUCY2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 12-14628744-G-GA is Benign according to our data. Variant chr12-14628744-G-GA is described in ClinVar as Benign. ClinVar VariationId is 402915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4 link	c.2158-8dupT		splice_region_variant, intron_variant	Intron 19 of 26	ENST00000261170.5	NP_004954.2	P25092
GUCY2C	XM_011520631.3 link	c.1912-8dupT		splice_region_variant, intron_variant	Intron 19 of 26		XP_011518933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2C	ENST00000261170.5 link	c.2158-8_2158-7insT		splice_region_variant, intron_variant	Intron 19 of 26	1	NM_004963.4	ENSP00000261170.3		P25092

Frequencies

GnomAD3 genomes

AF:

0.516

AC:

77720

AN:

150654

Hom.:

20588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.609

Gnomad AMI

AF:

0.690

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.453

Gnomad MID

AF:

0.465

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.500

GnomAD2 exomes

AF:

0.447

AC:

96986

AN:

216742

AF XY:

0.439

show subpopulations

Gnomad AFR exome

AF:

0.558

Gnomad AMR exome

AF:

0.628

Gnomad ASJ exome

AF:

0.451

Gnomad EAS exome

AF:

0.268

Gnomad FIN exome

AF:

0.432

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.437

GnomAD4 exome

AF:

0.408

AC:

481838

AN:

1181968

Hom.:

83127

Cov.:

AF XY:

0.409

AC XY:

245394

AN XY:

599572

show subpopulations

African (AFR)

AF:

0.533

AC:

13973

AN:

26202

American (AMR)

AF:

0.618

AC:

24873

AN:

40216

Ashkenazi Jewish (ASJ)

AF:

0.447

AC:

10501

AN:

23492

East Asian (EAS)

AF:

0.300

AC:

11252

AN:

37530

South Asian (SAS)

AF:

0.421

AC:

32538

AN:

77202

European-Finnish (FIN)

AF:

0.431

AC:

22056

AN:

51154

Middle Eastern (MID)

AF:

0.435

AC:

2231

AN:

5124

European-Non Finnish (NFE)

AF:

0.394

AC:

343455

AN:

870658

Other (OTH)

AF:

0.416

AC:

20959

AN:

50390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

12628

25257

37885

50514

63142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9968

19936

29904

39872

49840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.516

AC:

77834

AN:

150768

Hom.:

20634

Cov.:

AF XY:

0.517

AC XY:

37996

AN XY:

73550

show subpopulations

African (AFR)

AF:

0.609

AC:

25051

AN:

41120

American (AMR)

AF:

0.635

AC:

9601

AN:

15114

Ashkenazi Jewish (ASJ)

AF:

0.496

AC:

1715

AN:

3456

East Asian (EAS)

AF:

0.279

AC:

1432

AN:

5124

South Asian (SAS)

AF:

0.461

AC:

2203

AN:

4778

European-Finnish (FIN)

AF:

0.453

AC:

4636

AN:

10234

Middle Eastern (MID)

AF:

0.476

AC:

138

AN:

290

European-Non Finnish (NFE)

AF:

0.464

AC:

31383

AN:

67660

Other (OTH)

AF:

0.504

AC:

1053

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1770

3541

5311

7082

8852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.441

Hom.:

8258

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Congenital diarrhea 6

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.99

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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