rs5996074

Variant names:

• chr22-41840333-G-A
• rs5996074
• NM_004599.4:c.88+6975G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-41840333-G-A
• chr22-41840333-G-C

Variant summary

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

The NM_004599.4(SREBF2):​c.88+6975G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,034 control chromosomes in the GnomAD database, including 41,840 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (41840 hom., cov: 31)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 10 publications found

Genes affected

SREBF2 (HGNC:11290): (sterol regulatory element binding transcription factor 2) This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SREBF2 Gene-Disease associations (from GenCC):

• neurocutaneous syndrome

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004599.4. 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
	SREBF2	NM_004599.4	MANE Select	c.88+6975G>A		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.254+6975G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF2	ENST00000361204.9	TSL:1 MANE Select	c.88+6975G>A		intron	N/A	ENSP00000354476.4	Q12772-1
	SREBF2	ENST00000424354.5	TSL:1	n.88+6975G>A		intron	N/A	ENSP00000395728.1	G3V0I8
	SREBF2	ENST00000925855.1		c.88+6975G>A		intron	N/A	ENSP00000595914.1

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112028 AN: 151916 Hom.: 41772 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.747

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.738 AC: 112159 AN: 152034 Hom.: 41840 Cov.: 31 AF XY: 0.738 AC XY: 54833 AN XY: 74314

African (AFR) AF: 0.816 AC: 33838 AN: 41488

American (AMR) AF: 0.811 AC: 12389 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2448 AN: 3472

East Asian (EAS) AF: 0.518 AC: 2674 AN: 5160

South Asian (SAS) AF: 0.763 AC: 3687 AN: 4832

European-Finnish (FIN) AF: 0.680 AC: 7171 AN: 10538

Middle Eastern (MID) AF: 0.719 AC: 210 AN: 292

European-Non Finnish (NFE) AF: 0.698 AC: 47460 AN: 67954

Other (OTH) AF: 0.750 AC: 1582 AN: 2108

Alfa AF: 0.710 Hom.: 5446

Bravo AF: 0.752

Asia WGS AF: 0.704 AC: 2444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.088
DANN	Benign	0.20
PhyloP100		-1.5
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: rs5996074; hg19: chr22-42236337; COSMIC: COSV107459492;