chr19-41206370-C-T

Position:

• chr19-41206370-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028252304).
• BP6: Variant 19-41206370-C-T is Benign according to our data. Variant chr19-41206370-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2S1	NM_030622.8	c.1397C>T	p.Pro466Leu	missense_variant	9/9	ENST00000310054.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2S1	ENST00000310054.9	c.1397C>T	p.Pro466Leu	missense_variant	9/9	1	NM_030622.8	P1
CYP2S1	ENST00000593890.1	c.*91C>T		3_prime_UTR_variant	3/3	3
CYP2S1	ENST00000593545.5	c.*408C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	2

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

GnomAD3 exomes AF: 0.0213 AC: 5354 AN: 251292 Hom.: 74 AF XY: 0.0227 AC XY: 3083 AN XY: 135826

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 SAS exome AF: 0.0297

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

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0218

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

Gnomad4 AFR AF: 0.0250

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0265

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0209 Hom.: 18

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 v4.3

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
MutationTaster	Benign	1.0	N;N
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

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

Other links and lift over

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