19-41206370-C-T

Variant names:

• chr19-41206370-C-T
• rs34971233
• NM_030622.8:c.1397C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030622.8(CYP2S1):​c.1397C>T​(p.Pro466Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,614,086 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (46 hom., cov: 31)
  • Exomes 𝑓: 0.022 (406 hom.)
• Consequence: CYP2S1 NM_030622.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028252304).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0227 (3457/152204) while in subpopulation SAS AF = 0.0265 (128/4828). AF 95% confidence interval is 0.0237. There are 46 homozygotes in GnomAd4. There are 1684 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030622.8. 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
	CYP2S1	NM_030622.8	MANE Select	c.1397C>T	p.Pro466Leu	missense	Exon 9 of 9	NP_085125.1	Q96SQ9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP2S1	ENST00000310054.9	TSL:1 MANE Select	c.1397C>T	p.Pro466Leu	missense	Exon 9 of 9	ENSP00000308032.3	Q96SQ9-1
	CYP2S1	ENST00000922089.1		c.1394C>T	p.Pro465Leu	missense	Exon 9 of 9	ENSP00000592148.1
	CYP2S1	ENST00000922088.1		c.1217C>T	p.Pro406Leu	missense	Exon 8 of 8	ENSP00000592147.1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3449 AN: 152086 Hom.: 44 Cov.: 31

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0213 AC: 5354 AN: 251292 AF XY: 0.0227

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0222 AC: 32472 AN: 1461882 Hom.: 406 Cov.: 38 AF XY: 0.0228 AC XY: 16617 AN XY: 727242

African (AFR) AF: 0.0254 AC: 850 AN: 33480

American (AMR) AF: 0.0142 AC: 637 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 501 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0304 AC: 2620 AN: 86258

European-Finnish (FIN) AF: 0.0255 AC: 1361 AN: 53408

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 24994 AN: 1112012

Other (OTH) AF: 0.0218 AC: 1316 AN: 60396

GnomAD4 genome AF: 0.0227 AC: 3457 AN: 152204 Hom.: 46 Cov.: 31 AF XY: 0.0226 AC XY: 1684 AN XY: 74414

African (AFR) AF: 0.0250 AC: 1038 AN: 41500

American (AMR) AF: 0.0211 AC: 322 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4828

European-Finnish (FIN) AF: 0.0237 AC: 251 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1576 AN: 68018

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0210 Hom.: 22

Bravo AF: 0.0226

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.0229 AC: 197

ExAC AF: 0.0225 AC: 2727

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0254

EpiControl AF: 0.0226

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.58	N
PhyloP100		1.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.17
Sift	Benign	0.69	T
Sift4G	Benign	0.87	T
Polyphen		1.0	D
Vest4		0.089
MPC		0.99
ClinPred		0.040	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.41
Mutation Taster		=97/3	polymorphism (auto)

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: rs34971233; hg19: chr19-41712275; COSMIC: COSV99047607; COSMIC: COSV99047607;