11-106687745-C-A

Position:

• chr11-106687745-C-A

Variant summary

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

The NM_000855.3(GUCY1A2):​c.2003G>T​(p.Arg668Leu) 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. 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: 4.55

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=0.22795507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY1A2	NM_000855.3	c.2003G>T	p.Arg668Leu	missense_variant	8/8	ENST00000526355.7	NP_000846.1
GUCY1A2	NM_001256424.2	c.2096G>T	p.Arg699Leu	missense_variant	9/9		NP_001243353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY1A2	ENST00000526355.7	c.2003G>T	p.Arg668Leu	missense_variant	8/8	1	NM_000855.3	ENSP00000431245.2
GUCY1A2	ENST00000282249.6	c.2096G>T	p.Arg699Leu	missense_variant	9/9	1		ENSP00000282249.2
GUCY1A2	ENST00000347596.2	c.2066G>T	p.Arg689Leu	missense_variant	9/9	1		ENSP00000344874.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Dec 21, 2023

The c.2003G>T (p.R668L) alteration is located in exon 8 (coding exon 8) of the GUCY1A2 gene. This alteration results from a G to T substitution at nucleotide position 2003, causing the arginine (R) at amino acid position 668 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	0.11
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.092
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	-0.010	N;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.030	B;B;.
Vest4		0.34
MutPred		0.45		Loss of disorder (P = 0.038);.;.;
MVP		0.86
MPC		0.67
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.41

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: chr11-106558471;