12-14613277-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004963.4(GUCY2C):c.3062G>A(p.Arg1021His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

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]

PLBD1-AS1 (HGNC:51143): (PLBD1 antisense RNA 1)

C12orf60 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053353637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2C	NM_004963.4	c.3062G>A	p.Arg1021His	missense_variant	27/27	ENST00000261170.5
PLBD1-AS1	NR_120465.1	n.297+351C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2C	ENST00000261170.5	c.3062G>A	p.Arg1021His	missense_variant	27/27	1	NM_004963.4	P1
PLBD1-AS1	ENST00000660979.1	n.732-5875C>T		intron_variant, non_coding_transcript_variant
PLBD1-AS1	ENST00000542401.2	n.848+351C>T		intron_variant, non_coding_transcript_variant		4
PLBD1-AS1	ENST00000545424.5	n.279+351C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 250756 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135504

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1460402 Hom.: 1 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 726618

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000792

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1021 of the GUCY2C protein (p.Arg1021His). This variant is present in population databases (rs118078831, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with GUCY2C-related conditions. ClinVar contains an entry for this variant (Variation ID: 2073348). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.14	T
Sift4G	Benign	0.084	T
Polyphen		0.12	B
Vest4		0.076
MVP		0.85
MPC		0.28
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs118078831; hg19: chr12-14766211;