22-24547981-A-T

Variant names:

• chr22-24547981-A-T
• rs2044773550
• NM_001284254.2:c.221T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001284254.2(GUCD1):​c.221T>A​(p.Leu74Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCD1 NM_001284254.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.78
• Publications: 0 publications found

Genes affected

GUCD1 (HGNC:14237): (guanylyl cyclase domain containing 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001284254.2. 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
	GUCD1	NM_001284254.2	MANE Select	c.221T>A	p.Leu74Gln	missense	Exon 3 of 6	NP_001271183.1	Q96NT3-2
	GUCD1	NM_001284251.2		c.389T>A	p.Leu130Gln	missense	Exon 3 of 6	NP_001271180.1	A0A087WVD9
	GUCD1	NM_001284252.2		c.389T>A	p.Leu130Gln	missense	Exon 3 of 6	NP_001271181.1	Q96NT3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCD1	ENST00000435822.6	TSL:1 MANE Select	c.221T>A	p.Leu74Gln	missense	Exon 3 of 6	ENSP00000405985.1	Q96NT3-2
	GUCD1	ENST00000621833.4	TSL:1	c.389T>A	p.Leu130Gln	missense	Exon 3 of 6	ENSP00000479370.1	A0A087WVD9
	GUCD1	ENST00000404664.7	TSL:2	c.389T>A	p.Leu130Gln	missense	Exon 3 of 6	ENSP00000384121.3	Q96NT3-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.89		Loss of stability (P = 0.0399)
MVP		0.60
MPC		0.88
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.87
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs2044773550; hg19: chr22-24943949;