chr11-106810252-C-G

Position:

• chr11-106810252-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000855.3(GUCY1A2):​c.1433G>C​(p.Arg478Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUCY1A2 NM_000855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17

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]

ACMG classification

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=0.15444073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY1A2	NM_000855.3	c.1433G>C	p.Arg478Thr	missense_variant	5/8	ENST00000526355.7	NP_000846.1
GUCY1A2	NM_001256424.2	c.1433G>C	p.Arg478Thr	missense_variant	5/9		NP_001243353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.1433G>C	p.Arg478Thr	missense_variant	5/8	1	NM_000855.3	ENSP00000431245.2
GUCY1A2	ENST00000282249.6	c.1433G>C	p.Arg478Thr	missense_variant	5/9	1		ENSP00000282249.2
GUCY1A2	ENST00000347596.2	c.1496G>C	p.Arg499Thr	missense_variant	6/9	1		ENSP00000344874.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1433G>C (p.R478T) alteration is located in exon 5 (coding exon 5) of the GUCY1A2 gene. This alteration results from a G to C substitution at nucleotide position 1433, causing the arginine (R) at amino acid position 478 to be replaced by a threonine (T). 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	0.20
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	-0.26	N;N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.081	B;B;.
Vest4		0.30
MutPred		0.65		Loss of MoRF binding (P = 0.0186);Loss of MoRF binding (P = 0.0186);.;
MVP		0.76
MPC		0.79
ClinPred		0.29	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-106680978;