19-41198491-G-C

Position:

• chr19-41198491-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030622.8(CYP2S1):​c.523G>C​(p.Ala175Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2S1 NM_030622.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.941

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2S1	NM_030622.8	c.523G>C	p.Ala175Pro	missense_variant	4/9	ENST00000310054.9	NP_085125.1
CYP2S1	XM_047438711.1	c.523G>C	p.Ala175Pro	missense_variant	4/7		XP_047294667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2S1	ENST00000310054.9	c.523G>C	p.Ala175Pro	missense_variant	4/9	1	NM_030622.8	ENSP00000308032	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2022

The c.523G>C (p.A175P) alteration is located in exon 4 (coding exon 4) of the CYP2S1 gene. This alteration results from a G to C substitution at nucleotide position 523, causing the alanine (A) at amino acid position 175 to be replaced by a proline (P). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.53
Sift	Benign	0.031	D
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.51
MutPred		0.52		Gain of disorder (P = 0.0947);
MVP		0.51
MPC		0.44
ClinPred		0.71	D
GERP RS		2.8
Varity_R		0.74
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: 6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-41704396;