chr22-41873624-C-A

Variant names:

• chr22-41873624-C-A
• rs133291
• NM_004599.4:c.868-174C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004599.4(SREBF2):​c.868-174C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000198 in 503,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.59
• Publications: 27 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.868-174C>A		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.1034-174C>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.868-174C>A		intron	N/A	ENSP00000354476.4	Q12772-1
	SREBF2	ENST00000424354.5	TSL:1	n.868-174C>A		intron	N/A	ENSP00000395728.1	G3V0I8
	SREBF2	ENST00000925855.1		c.868-174C>A		intron	N/A	ENSP00000595914.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000198 AC: 1 AN: 503790 Hom.: 0 AF XY: 0.00000375 AC XY: 1 AN XY: 267002

African (AFR) AF: 0.00 AC: 0 AN: 14050

American (AMR) AF: 0.00 AC: 0 AN: 26020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16192

East Asian (EAS) AF: 0.00 AC: 0 AN: 31246

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 300042

Other (OTH) AF: 0.00 AC: 0 AN: 28054

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.010
DANN	Benign	0.57
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs133291; hg19: chr22-42269628;