12-14628744-GA-GAAAAA

Variant names:

• chr12-14628744-G-GAAAA
• rs3217210
• NM_004963.4:c.2158-11_2158-8dupTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004963.4(GUCY2C):​c.2158-11_2158-8dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: GUCY2C NM_004963.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.995
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2C	NM_004963.4	c.2158-11_2158-8dupTTTT		splice_region_variant, intron_variant	Intron 19 of 26	ENST00000261170.5	NP_004954.2
GUCY2C	XM_011520631.3	c.1912-11_1912-8dupTTTT		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_2158-7insTTTT		splice_region_variant, intron_variant	Intron 19 of 26	1	NM_004963.4	ENSP00000261170.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00 AC: 0 AN: 216742 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000252 AC: 3 AN: 1188984 Hom.: 0 Cov.: 20 AF XY: 0.00000166 AC XY: 1 AN XY: 603110

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

African (AFR) AF: 0.0000380 AC: 1 AN: 26316

American (AMR) AF: 0.0000248 AC: 1 AN: 40386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23672

East Asian (EAS) AF: 0.00 AC: 0 AN: 37846

South Asian (SAS) AF: 0.00 AC: 0 AN: 77792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5142

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 875654

Other (OTH) AF: 0.00 AC: 0 AN: 50728

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99

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;