11-106708608-G-A

Position:

• chr11-106708608-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000855.3(GUCY1A2):​c.1895C>T​(p.Pro632Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: GUCY1A2 NM_000855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.95

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY1A2	NM_000855.3	c.1895C>T	p.Pro632Leu	missense_variant	7/8	ENST00000526355.7	NP_000846.1
GUCY1A2	NM_001256424.2	c.1988C>T	p.Pro663Leu	missense_variant	8/9		NP_001243353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.1895C>T	p.Pro632Leu	missense_variant	7/8	1	NM_000855.3	ENSP00000431245.2
GUCY1A2	ENST00000282249.6	c.1988C>T	p.Pro663Leu	missense_variant	8/9	1		ENSP00000282249.2
GUCY1A2	ENST00000347596.2	c.1958C>T	p.Pro653Leu	missense_variant	8/9	1		ENSP00000344874.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

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 28, 2024

The c.1895C>T (p.P632L) alteration is located in exon 7 (coding exon 7) of the GUCY1A2 gene. This alteration results from a C to T substitution at nucleotide position 1895, causing the proline (P) at amino acid position 632 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.3	D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.046	D;D;D
Sift4G	Uncertain	0.049	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.53		Gain of MoRF binding (P = 0.0493);.;.;
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.49
gMVP		0.90

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: chr11-106579334;