NM_000857.5:c.1480C>G

Variant names:

• chr4-155803690-C-G
• rs371047617
• NM_000857.5:c.1480C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000857.5(GUCY1B1):​c.1480C>G​(p.Arg494Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,601,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: GUCY1B1 NM_000857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• Publications: 1 publications found

Genes affected

GUCY1B1 (HGNC:4687): (guanylate cyclase 1 soluble subunit beta 1) This gene encodes the beta subunit of the soluble guanylate cyclase (sGC), which catalyzes the conversion of GTP (guanosine triphosphate) to cGMP (cyclic guanosine monophosphate). The encoded protein contains an HNOX domain, which serves as a receptor for ligands such as nitric oxide, oxygen and nitrovasodilator drugs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000857.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1B1	NM_000857.5	MANE Select	c.1480C>G	p.Arg494Gly	missense	Exon 11 of 14	NP_000848.1	Q02153-1
	GUCY1B1	NM_001291951.3		c.1546C>G	p.Arg516Gly	missense	Exon 12 of 15	NP_001278880.1	E9PCN2
	GUCY1B1	NM_001291952.3		c.1420C>G	p.Arg474Gly	missense	Exon 12 of 15	NP_001278881.1	Q02153-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1B1	ENST00000264424.13	TSL:1 MANE Select	c.1480C>G	p.Arg494Gly	missense	Exon 11 of 14	ENSP00000264424.8	Q02153-1
	GUCY1B1	ENST00000507146.5	TSL:1	c.1405C>G	p.Arg469Gly	missense	Exon 12 of 15	ENSP00000422313.1	D6RC99
	GUCY1B1	ENST00000503520.5	TSL:1	c.1381C>G	p.Arg461Gly	missense	Exon 11 of 14	ENSP00000420842.1	Q02153-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000765 AC: 18 AN: 235250 AF XY: 0.0000629

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.0000615

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000931 AC: 135 AN: 1449518 Hom.: 0 Cov.: 29 AF XY: 0.0000916 AC XY: 66 AN XY: 720466

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.0000459 AC: 2 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 84270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000116 AC: 128 AN: 1104726

Other (OTH) AF: 0.0000834 AC: 5 AN: 59932

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000252 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000911 AC: 11

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.53
Sift	Benign	0.031	D
Sift4G	Benign	0.11	T
Polyphen		0.052	B
Vest4		0.68
MVP		0.77
MPC		1.1
ClinPred		0.072	T
GERP RS		3.9
Varity_R		0.78
gMVP		0.89
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371047617; hg19: chr4-156724842;