Variant 11-107017857-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000855.3(GUCY1A2):c.199G>T(p.Ala67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,251,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

GUCY1A2
NM_000855.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.732

Variant links:

Genes affected

GUCY1A2 (HGNC:4684): (guanylate cyclase 1 soluble subunit alpha 2) Soluble guanylate cyclases are heterodimeric proteins that catalyze the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. The protein encoded by this gene is an alpha subunit of this complex and it interacts with a beta subunit to form the guanylate cyclase enzyme, which is activated by nitric oxide. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

GUCY1A2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11514774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY1A2	NM_000855.3 linkuse as main transcript	c.199G>T	p.Ala67Ser	missense_variant	1/8	ENST00000526355.7
GUCY1A2	NM_001256424.2 linkuse as main transcript	c.199G>T	p.Ala67Ser	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY1A2	ENST00000526355.7 linkuse as main transcript	c.199G>T	p.Ala67Ser	missense_variant	1/8	1	NM_000855.3	P1	P33402-1
GUCY1A2	ENST00000282249.6 linkuse as main transcript	c.199G>T	p.Ala67Ser	missense_variant	1/9	1			P33402-2
GUCY1A2	ENST00000347596.2 linkuse as main transcript	c.199G>T	p.Ala67Ser	missense_variant	1/9	1			P33402-3

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

238

AN:

1100206

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

113

AN XY:

524528

show subpopulations

Gnomad4 AFR exome

AF:

0.0000438

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.000388

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151660

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74106

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000277

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000264

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.199G>T (p.A67S) alteration is located in exon 1 (coding exon 1) of the GUCY1A2 gene. This alteration results from a G to T substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Benign

0.63

DEOGEN2

Benign

0.055

T;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.41

T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.90

L;L;L

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.28

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.0030

B;B;.

Vest4

0.17

MutPred

0.26

Gain of glycosylation at A67 (P = 2e-04);Gain of glycosylation at A67 (P = 2e-04);Gain of glycosylation at A67 (P = 2e-04);

MVP

0.63

MPC

0.49

ClinPred

0.069

GERP RS

0.043

Varity_R

0.045

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over