rs2162459

Variant names:

• chr8-58498483-G-A
• rs2162459
• NM_000780.4:c.81-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-58498483-G-A
• chr8-58498483-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000780.4(CYP7A1):​c.81-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,612,524 control chromosomes in the GnomAD database, including 267,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22119 hom., cov: 32)
  • Exomes 𝑓: 0.58 (245415 hom.)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.35
• Publications: 18 publications found

Genes affected

CYP7A1 (HGNC:2651): (cytochrome P450 family 7 subfamily A 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 endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway in the liver, which converts cholesterol to bile acids. This reaction is the rate limiting step and the major site of regulation of bile acid synthesis, which is the primary mechanism for the removal of cholesterol from the body. Polymorphisms in the promoter of this gene are associated with defects in bile acid synthesis. [provided by RefSeq, Feb 2010]

CYP7A1 Gene-Disease associations (from GenCC):

• hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency

  Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-58498483-G-A is Benign according to our data. Variant chr8-58498483-G-A is described in ClinVar as Benign. ClinVar VariationId is 1244824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP7A1	NM_000780.4	c.81-14C>T		intron_variant	Intron 1 of 5	ENST00000301645.4	NP_000771.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP7A1	ENST00000301645.4	c.81-14C>T		intron_variant	Intron 1 of 5	1	NM_000780.4	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80756 AN: 151888 Hom.: 22098 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.562 AC: 140940 AN: 250832 AF XY: 0.557

Gnomad AFR exome AF: 0.412

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.634

Gnomad EAS exome AF: 0.438

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.576 AC: 841650 AN: 1460518 Hom.: 245415 Cov.: 43 AF XY: 0.573 AC XY: 416029 AN XY: 726576

African (AFR) AF: 0.407 AC: 13619 AN: 33438

American (AMR) AF: 0.711 AC: 31778 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 16663 AN: 26126

East Asian (EAS) AF: 0.432 AC: 17124 AN: 39680

South Asian (SAS) AF: 0.493 AC: 42507 AN: 86220

European-Finnish (FIN) AF: 0.501 AC: 26672 AN: 53288

Middle Eastern (MID) AF: 0.614 AC: 3538 AN: 5764

European-Non Finnish (NFE) AF: 0.590 AC: 655103 AN: 1110934

Other (OTH) AF: 0.574 AC: 34646 AN: 60354

GnomAD4 genome AF: 0.532 AC: 80808 AN: 152006 Hom.: 22119 Cov.: 32 AF XY: 0.528 AC XY: 39245 AN XY: 74276

African (AFR) AF: 0.413 AC: 17122 AN: 41426

American (AMR) AF: 0.654 AC: 9986 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2228 AN: 3468

East Asian (EAS) AF: 0.431 AC: 2230 AN: 5174

South Asian (SAS) AF: 0.506 AC: 2439 AN: 4818

European-Finnish (FIN) AF: 0.486 AC: 5132 AN: 10566

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39746 AN: 67958

Other (OTH) AF: 0.561 AC: 1186 AN: 2114

Alfa AF: 0.575 Hom.: 43452

Bravo AF: 0.539

Asia WGS AF: 0.514 AC: 1787 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	13
DANN	Benign	0.59
PhyloP100		1.4
Mutation Taster		=100/0	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: rs2162459; hg19: chr8-59411042; COSMIC: COSV56962872;