12-14613124-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004963.4(GUCY2C):c.3215A>G(p.Tyr1072Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,612,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: GUCY2C NM_004963.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.49

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011215597).
• BP6: Variant 12-14613124-T-C is Benign according to our data. Variant chr12-14613124-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 782874.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000348 (53/152300) while in subpopulation EAS AF= 0.00503 (26/5172). AF 95% confidence interval is 0.00352. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2C	NM_004963.4	c.3215A>G	p.Tyr1072Cys	missense_variant	27/27	ENST00000261170.5
PLBD1-AS1	NR_120465.1	n.297+198T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2C	ENST00000261170.5	c.3215A>G	p.Tyr1072Cys	missense_variant	27/27	1	NM_004963.4	P1
PLBD1-AS1	ENST00000660979.1	n.732-6028T>C		intron_variant, non_coding_transcript_variant
PLBD1-AS1	ENST00000542401.2	n.848+198T>C		intron_variant, non_coding_transcript_variant		4
PLBD1-AS1	ENST00000545424.5	n.279+198T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000399 AC: 100 AN: 250884 Hom.: 2 AF XY: 0.000332 AC XY: 45 AN XY: 135596

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00473

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000149 AC: 217 AN: 1460432 Hom.: 2 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 726630

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00254

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74472

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00503

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000239 Hom.: 1

Bravo AF: 0.000408

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.95
MPC		0.75
ClinPred		0.068	T
GERP RS		5.7
Varity_R		0.22
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs35179392; hg19: chr12-14766058;