rs10772800

Variant names:

• chr12-14641128-G-A
• rs10772800
• NM_004963.4:c.2022C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-14641128-G-A
• chr12-14641128-G-C
• chr12-14641128-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004963.4(GUCY2C):​c.2022C>T​(p.Ile674Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,613,586 control chromosomes in the GnomAD database, including 755,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (57809 hom., cov: 30)
  • Exomes 𝑓: 0.97 (698108 hom.)
• Consequence: GUCY2C NM_004963.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.410
• Publications: 17 publications found

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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• congenital sodium diarrhea

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-14641128-G-A is Benign according to our data. Variant chr12-14641128-G-A is described in ClinVar as Benign. ClinVar VariationId is 402916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	NM_004963.4	MANE Select	c.2022C>T	p.Ile674Ile	synonymous	Exon 18 of 27	NP_004954.2	P25092

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	ENST00000261170.5	TSL:1 MANE Select	c.2022C>T	p.Ile674Ile	synonymous	Exon 18 of 27	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.2022C>T	p.Ile674Ile	synonymous	Exon 18 of 28	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.2022C>T	p.Ile674Ile	synonymous	Exon 18 of 26	ENSP00000640842.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128078 AN: 151976 Hom.: 57806 Cov.: 30

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.976

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.966

Gnomad EAS AF: 0.989

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.989

Gnomad OTH AF: 0.880

GnomAD2 exomes AF: 0.950 AC: 238744 AN: 251312 AF XY: 0.960

Gnomad AFR exome AF: 0.466

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.970

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.988

Gnomad OTH exome AF: 0.970

GnomAD4 exome AF: 0.974 AC: 1423538 AN: 1461492 Hom.: 698108 Cov.: 42 AF XY: 0.976 AC XY: 709428 AN XY: 727050

African (AFR) AF: 0.459 AC: 15350 AN: 33442

American (AMR) AF: 0.969 AC: 43340 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 25364 AN: 26130

East Asian (EAS) AF: 0.989 AC: 39257 AN: 39692

South Asian (SAS) AF: 0.980 AC: 84482 AN: 86236

European-Finnish (FIN) AF: 0.988 AC: 52789 AN: 53420

Middle Eastern (MID) AF: 0.949 AC: 5314 AN: 5602

European-Non Finnish (NFE) AF: 0.989 AC: 1100097 AN: 1111888

Other (OTH) AF: 0.953 AC: 57545 AN: 60362

GnomAD4 genome AF: 0.842 AC: 128105 AN: 152094 Hom.: 57809 Cov.: 30 AF XY: 0.846 AC XY: 62942 AN XY: 74374

African (AFR) AF: 0.480 AC: 19867 AN: 41400

American (AMR) AF: 0.936 AC: 14313 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.966 AC: 3351 AN: 3470

East Asian (EAS) AF: 0.989 AC: 5100 AN: 5158

South Asian (SAS) AF: 0.977 AC: 4713 AN: 4822

European-Finnish (FIN) AF: 0.988 AC: 10493 AN: 10616

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.989 AC: 67233 AN: 68012

Other (OTH) AF: 0.881 AC: 1862 AN: 2114

Alfa AF: 0.930 Hom.: 180465

Bravo AF: 0.824

Asia WGS AF: 0.948 AC: 3296 AN: 3478

EpiCase AF: 0.988

EpiControl AF: 0.987

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital diarrhea 6 (1)
-	-	1	Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.6
DANN	Benign	0.82
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10772800; hg19: chr12-14794062; COSMIC: COSV108082254;