rs28941786

Variant names:

• chr1-70430388-C-G
• rs28941786
• NM_001902.6:c.718C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-70430388-C-G
• chr1-70430388-C-A
• chr1-70430388-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001902.6(CTH):​c.718C>G​(p.Gln240Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,393,214 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CTH NM_001902.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57
• Publications: 11 publications found

Genes affected

CTH (HGNC:2501): (cystathionine gamma-lyase) This gene encodes a cytoplasmic enzyme in the trans-sulfuration pathway that converts cystathione derived from methionine into cysteine. Glutathione synthesis in the liver is dependent upon the availability of cysteine. Mutations in this gene cause cystathioninuria. Alternative splicing of this gene results in three transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

CTH Gene-Disease associations (from GenCC):

• cystathioninuria

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen

ENSG00000306600 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 1-70430388-C-G is Pathogenic according to our data. Variant chr1-70430388-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2940.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001902.6. 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
	CTH	NM_001902.6	MANE Select	c.718C>G	p.Gln240Glu	missense	Exon 7 of 12	NP_001893.2
	CTH	NM_001190463.2		c.622C>G	p.Gln208Glu	missense	Exon 6 of 11	NP_001177392.1	P32929-3
	CTH	NM_153742.5		c.586C>G	p.Gln196Glu	missense	Exon 6 of 11	NP_714964.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTH	ENST00000370938.8	TSL:1 MANE Select	c.718C>G	p.Gln240Glu	missense	Exon 7 of 12	ENSP00000359976.3	P32929-1
	CTH	ENST00000346806.2	TSL:1	c.586C>G	p.Gln196Glu	missense	Exon 6 of 11	ENSP00000311554.2	P32929-2
	CTH	ENST00000896200.1		c.718C>G	p.Gln240Glu	missense	Exon 8 of 13	ENSP00000566259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251346 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1393214 Hom.: 0 Cov.: 23 AF XY: 0.00000143 AC XY: 1 AN XY: 697500

African (AFR) AF: 0.00 AC: 0 AN: 32144

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 84898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1049568

Other (OTH) AF: 0.00 AC: 0 AN: 58044

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cystathioninuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.87		Gain of methylation at R237 (P = 0.0747)
MVP		0.95
MPC		0.49
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.87
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs28941786; hg19: chr1-70896071;