chr11-106940110-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000855.3(GUCY1A2):c.556G>A(p.Glu186Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
GUCY1A2
NM_000855.3 missense
NM_000855.3 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 7.81
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.898
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GUCY1A2 | NM_000855.3 | c.556G>A | p.Glu186Lys | missense_variant | 4/8 | ENST00000526355.7 | |
GUCY1A2 | NM_001256424.2 | c.556G>A | p.Glu186Lys | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GUCY1A2 | ENST00000526355.7 | c.556G>A | p.Glu186Lys | missense_variant | 4/8 | 1 | NM_000855.3 | P1 | |
GUCY1A2 | ENST00000282249.6 | c.556G>A | p.Glu186Lys | missense_variant | 4/9 | 1 | |||
GUCY1A2 | ENST00000347596.2 | c.556G>A | p.Glu186Lys | missense_variant | 4/9 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250292Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135562
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460698Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726774
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
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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 | May 11, 2022 | The c.556G>A (p.E186K) alteration is located in exon 4 (coding exon 4) of the GUCY1A2 gene. This alteration results from a G to A substitution at nucleotide position 556, causing the glutamic acid (E) at amino acid position 186 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Benign
T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;P;.
Vest4
MutPred
Gain of methylation at E186 (P = 0.0266);Gain of methylation at E186 (P = 0.0266);Gain of methylation at E186 (P = 0.0266);
MVP
MPC
0.97
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at