chr22-41841765-C-T

Variant names:

• chr22-41841765-C-T
• rs2267439
• NM_004599.4:c.88+8407C>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+8407C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.735 in 152,166 control chromosomes in the GnomAD database, including 41,565 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 (41565 hom., cov: 34)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450
• Publications: 18 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.8 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+8407C>T		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.254+8407C>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+8407C>T		intron	N/A	ENSP00000354476.4	Q12772-1
	SREBF2	ENST00000424354.5	TSL:1	n.88+8407C>T		intron	N/A	ENSP00000395728.1	G3V0I8
	SREBF2	ENST00000925855.1		c.88+8407C>T		intron	N/A	ENSP00000595914.1

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111774 AN: 152048 Hom.: 41520 Cov.: 34

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.726

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: 0.735 AC: 111877 AN: 152166 Hom.: 41565 Cov.: 34 AF XY: 0.735 AC XY: 54692 AN XY: 74392

African (AFR) AF: 0.807 AC: 33492 AN: 41498

American (AMR) AF: 0.810 AC: 12393 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2447 AN: 3468

East Asian (EAS) AF: 0.519 AC: 2687 AN: 5182

South Asian (SAS) AF: 0.762 AC: 3674 AN: 4820

European-Finnish (FIN) AF: 0.681 AC: 7198 AN: 10574

Middle Eastern (MID) AF: 0.723 AC: 211 AN: 292

European-Non Finnish (NFE) AF: 0.698 AC: 47491 AN: 68016

Other (OTH) AF: 0.750 AC: 1583 AN: 2110

Alfa AF: 0.701 Hom.: 20419

Bravo AF: 0.749

Asia WGS AF: 0.702 AC: 2439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	5.7
DANN	Benign	0.48
PhyloP100		0.45
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: rs2267439; hg19: chr22-42237769; COSMIC: COSV107459494;