rs2297810

Variant names:

• chr1-46815187-G-A
• rs2297810
• NM_001099772.2:c.996G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001099772.2(CYP4B1):​c.996G>A​(p.Met332Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,611,698 control chromosomes in the GnomAD database, including 25,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M332V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (5290 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20041 hom.)
• Consequence: CYP4B1 NM_001099772.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09
• Publications: 42 publications found

Genes affected

CYP4B1 (HGNC:2644): (cytochrome P450 family 4 subfamily B 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. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028523207).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4B1	NM_001099772.2	c.996G>A	p.Met332Ile	missense_variant	Exon 8 of 12	ENST00000371923.9	NP_001093242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4B1	ENST00000371923.9	c.996G>A	p.Met332Ile	missense_variant	Exon 8 of 12	1	NM_001099772.2	ENSP00000360991.4

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35295 AN: 152024 Hom.: 5251 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.186 AC: 46498 AN: 249498 AF XY: 0.179

Gnomad AFR exome AF: 0.427

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.156 AC: 227614 AN: 1459556 Hom.: 20041 Cov.: 33 AF XY: 0.156 AC XY: 113064 AN XY: 726076

African (AFR) AF: 0.429 AC: 14364 AN: 33448

American (AMR) AF: 0.218 AC: 9711 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3704 AN: 25984

East Asian (EAS) AF: 0.288 AC: 11405 AN: 39652

South Asian (SAS) AF: 0.176 AC: 15160 AN: 86048

European-Finnish (FIN) AF: 0.146 AC: 7797 AN: 53384

Middle Eastern (MID) AF: 0.144 AC: 829 AN: 5756

European-Non Finnish (NFE) AF: 0.139 AC: 154099 AN: 1110472

Other (OTH) AF: 0.175 AC: 10545 AN: 60300

GnomAD4 genome AF: 0.233 AC: 35376 AN: 152142 Hom.: 5290 Cov.: 32 AF XY: 0.232 AC XY: 17249 AN XY: 74374

African (AFR) AF: 0.418 AC: 17332 AN: 41488

American (AMR) AF: 0.230 AC: 3519 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3472

East Asian (EAS) AF: 0.272 AC: 1404 AN: 5164

South Asian (SAS) AF: 0.177 AC: 851 AN: 4820

European-Finnish (FIN) AF: 0.143 AC: 1521 AN: 10600

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.142 AC: 9631 AN: 67994

Other (OTH) AF: 0.214 AC: 451 AN: 2112

Alfa AF: 0.170 Hom.: 13162

Bravo AF: 0.246

TwinsUK AF: 0.136 AC: 506

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.413 AC: 1819

ESP6500EA AF: 0.147 AC: 1265

ExAC AF: 0.191 AC: 23243

Asia WGS AF: 0.246 AC: 856 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.28	.;N;.
PhyloP100		8.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.051	T;T;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		0.032	B;B;B
Vest4		0.38
MutPred		0.23		.;Loss of catalytic residue at M331 (P = 0.0825);.;
MPC		0.11
ClinPred		0.051	T
GERP RS		4.0
Varity_R		0.43
gMVP		0.57
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2297810; hg19: chr1-47280859; COSMIC: COSV54721270; COSMIC: COSV54721270;