Genetic Variant NM_001902.6:c.316C>A (chr1-70418002-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001902.6(CTH):c.316C>A(p.Gln106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CTH
NM_001902.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.726

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.15265968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTH	NM_001902.6 link	c.316C>A	p.Gln106Lys	missense_variant	Exon 3 of 12	ENST00000370938.8	NP_001893.2	P32929-1
CTH	NM_153742.5 link	c.316C>A	p.Gln106Lys	missense_variant	Exon 3 of 11		NP_714964.2	P32929-2
CTH	NM_001190463.2 link	c.250+1965C>A		intron_variant	Intron 2 of 10		NP_001177392.1	P32929-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTH	ENST00000370938.8 link	c.316C>A	p.Gln106Lys	missense_variant	Exon 3 of 12	1	NM_001902.6	ENSP00000359976.3	P32929-1
CTH	ENST00000346806.2 link	c.316C>A	p.Gln106Lys	missense_variant	Exon 3 of 11	1		ENSP00000311554.2	P32929-2
CTH	ENST00000411986.6 link	c.250+1965C>A		intron_variant	Intron 2 of 10	2		ENSP00000413407.2	P32929-3
CTH	ENST00000464926.1 link	n.394+1965C>A		intron_variant	Intron 2 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251426

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.316C>A (p.Q106K) alteration is located in exon 3 (coding exon 3) of the CTH gene. This alteration results from a C to A substitution at nucleotide position 316, causing the glutamine (Q) at amino acid position 106 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.53

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.55

P;B

Vest4

0.29

MutPred

0.56

Gain of ubiquitination at Q106 (P = 0.0289);Gain of ubiquitination at Q106 (P = 0.0289);

MVP

0.85

MPC

0.33

ClinPred

0.28

GERP RS

3.7

Varity_R

0.54

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over