22-41838933-C-T

Variant names:

• chr22-41838933-C-T
• rs7287010
• NM_004599.4:c.88+5575C>T

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+5575C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,826 control chromosomes in the GnomAD database, including 29,904 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 (29904 hom., cov: 30)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.455
• Publications: 12 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.765 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+5575C>T		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.254+5575C>T		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+5575C>T		intron	N/A	ENSP00000354476.4	Q12772-1
	SREBF2	ENST00000424354.5	TSL:1	n.88+5575C>T		intron	N/A	ENSP00000395728.1	G3V0I8
	SREBF2	ENST00000925855.1		c.88+5575C>T		intron	N/A	ENSP00000595914.1

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93678 AN: 151708 Hom.: 29858 Cov.: 30

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.627

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

GnomAD4 genome AF: 0.618 AC: 93778 AN: 151826 Hom.: 29904 Cov.: 30 AF XY: 0.618 AC XY: 45837 AN XY: 74170

African (AFR) AF: 0.772 AC: 31970 AN: 41408

American (AMR) AF: 0.661 AC: 10075 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1869 AN: 3470

East Asian (EAS) AF: 0.328 AC: 1688 AN: 5152

South Asian (SAS) AF: 0.571 AC: 2745 AN: 4804

European-Finnish (FIN) AF: 0.591 AC: 6229 AN: 10536

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37207 AN: 67910

Other (OTH) AF: 0.631 AC: 1328 AN: 2104

Alfa AF: 0.592 Hom.: 5469

Bravo AF: 0.633

Asia WGS AF: 0.523 AC: 1820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.6
DANN	Benign	0.43
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7287010; hg19: chr22-42234937;