chr19-41198536-C-T

Variant names:

• chr19-41198536-C-T
• rs764102046
• NM_030622.8:c.568C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030622.8(CYP2S1):​c.568C>T​(p.Arg190Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CYP2S1 NM_030622.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

Genes affected

CYP2S1 (HGNC:15654): (cytochrome P450 family 2 subfamily S member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum. In rodents, the homologous protein has been shown to metabolize certain carcinogens; however, the specific function of the human protein has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2S1	NM_030622.8	c.568C>T	p.Arg190Cys	missense_variant	Exon 4 of 9	ENST00000310054.9	NP_085125.1
CYP2S1	XM_047438711.1	c.568C>T	p.Arg190Cys	missense_variant	Exon 4 of 7		XP_047294667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2S1	ENST00000310054.9	c.568C>T	p.Arg190Cys	missense_variant	Exon 4 of 9	1	NM_030622.8	ENSP00000308032.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.88		Loss of disorder (P = 0.0964);
MVP		0.36
MPC		0.78
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs764102046; hg19: chr19-41704441; COSMIC: COSV59506794; COSMIC: COSV59506794;