NM_004963.4:c.3062G>A

Variant names:

• chr12-14613277-C-T
• rs118078831
• NM_004963.4:c.3062G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1021C) has been classified 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.89
• 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]

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053353637).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000986 (15/152124) while in subpopulation EAS AF = 0.000387 (2/5166). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3062G>A	p.Arg1021His	missense	Exon 27 of 27	NP_004954.2	P25092
	PLBD1-AS1	NR_120465.1		n.297+351C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	ENST00000261170.5	TSL:1 MANE Select	c.3062G>A	p.Arg1021His	missense	Exon 27 of 27	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.3095G>A	p.Arg1032His	missense	Exon 28 of 28	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.2963G>A	p.Arg988His	missense	Exon 26 of 26	ENSP00000640842.1

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

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 250756 AF XY: 0.000192

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33414

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39694

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5758

European-Non Finnish (NFE) AF: 0.0000792 AC: 88 AN: 1110826

Other (OTH) AF: 0.000133 AC: 8 AN: 60310

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

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67996

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000200 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.9
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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs118078831; hg19: chr12-14766211;