12-14628744-GA-GAAA

Variant names:

• chr12-14628744-G-GAA
• rs3217210
• NM_004963.4:c.2158-9_2158-8dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004963.4(GUCY2C):​c.2158-9_2158-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0096 (7 hom.)
• Consequence: GUCY2C NM_004963.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.995
• Publications: 6 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, 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-14628744-G-GAA is Benign according to our data. Variant chr12-14628744-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 1169657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00744 (1122/150852) while in subpopulation AFR AF = 0.0243 (1000/41136). AF 95% confidence interval is 0.0231. There are 12 homozygotes in GnomAd4. There are 545 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.2158-9_2158-8dupTT		splice_region_variant, intron_variant	Intron 19 of 26	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.1912-9_1912-8dupTT		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	c.2158-8_2158-7insTT		splice_region_variant, intron_variant	Intron 19 of 26	1	NM_004963.4	ENSP00000261170.3

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1101 AN: 150738 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00344

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0000975

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000783

Gnomad OTH AF: 0.00242

GnomAD2 exomes AF: 0.00687 AC: 1488 AN: 216742 AF XY: 0.00588

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.0183

Gnomad ASJ exome AF: 0.00336

Gnomad EAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00962 AC: 11092 AN: 1153192 Hom.: 7 Cov.: 20 AF XY: 0.00917 AC XY: 5356 AN XY: 584336

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0412 AC: 1023 AN: 24850

American (AMR) AF: 0.0176 AC: 653 AN: 37054

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 162 AN: 22636

East Asian (EAS) AF: 0.00277 AC: 103 AN: 37156

South Asian (SAS) AF: 0.00792 AC: 587 AN: 74158

European-Finnish (FIN) AF: 0.00379 AC: 189 AN: 49808

Middle Eastern (MID) AF: 0.0138 AC: 69 AN: 5014

European-Non Finnish (NFE) AF: 0.00918 AC: 7835 AN: 853492

Other (OTH) AF: 0.00961 AC: 471 AN: 49024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00744 AC: 1122 AN: 150852 Hom.: 12 Cov.: 0 AF XY: 0.00741 AC XY: 545 AN XY: 73596

African (AFR) AF: 0.0243 AC: 1000 AN: 41136

American (AMR) AF: 0.00344 AC: 52 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5132

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4778

European-Finnish (FIN) AF: 0.0000975 AC: 1 AN: 10258

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000783 AC: 53 AN: 67678

Other (OTH) AF: 0.00239 AC: 5 AN: 2090

Alfa AF: 0.00434 Hom.: 8258

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3217210; hg19: chr12-14781678; COSMIC: COSV106056046;