11-106939885-T-G

Position:

• chr11-106939885-T-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.781A>C​(p.Ile261Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.08

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=0.22193915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY1A2	NM_000855.3	c.781A>C	p.Ile261Leu	missense_variant	4/8	ENST00000526355.7	NP_000846.1
GUCY1A2	NM_001256424.2	c.781A>C	p.Ile261Leu	missense_variant	4/9		NP_001243353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.781A>C	p.Ile261Leu	missense_variant	4/8	1	NM_000855.3	ENSP00000431245.2
GUCY1A2	ENST00000282249.6	c.781A>C	p.Ile261Leu	missense_variant	4/9	1		ENSP00000282249.2
GUCY1A2	ENST00000347596.2	c.781A>C	p.Ile261Leu	missense_variant	4/9	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

Jun 02, 2024

The c.781A>C (p.I261L) alteration is located in exon 4 (coding exon 4) of the GUCY1A2 gene. This alteration results from a A to C substitution at nucleotide position 781, causing the isoleucine (I) at amino acid position 261 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	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.071	T;.;.
Eigen	Benign	-0.029
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.65	N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.45	B;B;.
Vest4		0.49
MutPred		0.56		Loss of catalytic residue at I261 (P = 0.0231);Loss of catalytic residue at I261 (P = 0.0231);Loss of catalytic residue at I261 (P = 0.0231);
MVP		0.41
MPC		0.53
ClinPred		0.75	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.57

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: chr11-106810611;