rs1052717

Variant names:

• chr22-41885425-A-G
• rs1052717
• NM_004599.4:c.2208+414A>G

Variant summary

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

The NM_004599.4(SREBF2):​c.2208+414A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,174 control chromosomes in the GnomAD database, including 31,372 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 0.62 (31372 hom., cov: 33)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 23 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 = 0.833 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.2208+414A>G		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.2474+414A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF2	ENST00000361204.9	TSL:1 MANE Select	c.2208+414A>G		intron	N/A	ENSP00000354476.4	Q12772-1
	SREBF2	ENST00000424354.5	TSL:1	n.*253+414A>G		intron	N/A	ENSP00000395728.1	G3V0I8
	SREBF2	ENST00000925855.1		c.2226+414A>G		intron	N/A	ENSP00000595914.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94646 AN: 152056 Hom.: 31312 Cov.: 33

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.585

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

GnomAD4 genome AF: 0.623 AC: 94760 AN: 152174 Hom.: 31372 Cov.: 33 AF XY: 0.620 AC XY: 46134 AN XY: 74384

African (AFR) AF: 0.840 AC: 34904 AN: 41534

American (AMR) AF: 0.678 AC: 10372 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2165 AN: 3468

East Asian (EAS) AF: 0.724 AC: 3757 AN: 5186

South Asian (SAS) AF: 0.558 AC: 2690 AN: 4822

European-Finnish (FIN) AF: 0.457 AC: 4828 AN: 10568

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.503 AC: 34212 AN: 67978

Other (OTH) AF: 0.578 AC: 1221 AN: 2112

Alfa AF: 0.551 Hom.: 92233

Bravo AF: 0.652

Asia WGS AF: 0.617 AC: 2148 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	0.59
DANN	Benign	0.48
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1052717; hg19: chr22-42281429;