12-14628744-GA-GAA

Variant names:

• chr12-14628744-G-GA
• rs3217210
• NM_004963.4:c.2158-8dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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, 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 -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.

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.2158-8dupT		splice_region intron	N/A	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.2158-8_2158-7insT		splice_region intron	N/A	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.2191-8_2191-7insT		splice_region intron	N/A	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.2158-8_2158-7insT		splice_region intron	N/A	ENSP00000640842.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 77720 AN: 150654 Hom.: 20588 Cov.: 0

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

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.: 20 AF XY: 0.409 AC XY: 245394 AN XY: 599572

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

GnomAD4 genome AF: 0.516 AC: 77834 AN: 150768 Hom.: 20634 Cov.: 0 AF XY: 0.517 AC XY: 37996 AN XY: 73550

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

Alfa AF: 0.441 Hom.: 8258

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
PhyloP100		-0.99
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: rs3217210; hg19: chr12-14781678; COSMIC: COSV106056045;