22-41891450-A-G

Variant names:

• chr22-41891450-A-G
• rs2267443
• NM_004599.4:c.2209-1667A>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.2209-1667A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 151,982 control chromosomes in the GnomAD database, including 34,247 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 0.67 (34245 hom., cov: 31)
  • Exomes 𝑓: 0.64 (2 hom.)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 17 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):

• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF2	NM_004599.4	MANE Select	c.2209-1667A>G		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.2475-1667A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF2	ENST00000361204.9	TSL:1 MANE Select	c.2209-1667A>G		intron	N/A	ENSP00000354476.4
	SREBF2	ENST00000424354.5	TSL:1	n.*254-1667A>G		intron	N/A	ENSP00000395728.1
	SREBF2	ENST00000491541.1	TSL:1	n.759+51A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101117 AN: 151850 Hom.: 34199 Cov.: 31

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.607

GnomAD4 exome AF: 0.643 AC: 9 AN: 14 Hom.: 2 AF XY: 0.600 AC XY: 6 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.667 AC: 4 AN: 6

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.666 AC: 101214 AN: 151968 Hom.: 34245 Cov.: 31 AF XY: 0.665 AC XY: 49408 AN XY: 74280

African (AFR) AF: 0.770 AC: 31927 AN: 41458

American (AMR) AF: 0.713 AC: 10894 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2261 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3500 AN: 5148

South Asian (SAS) AF: 0.578 AC: 2790 AN: 4824

European-Finnish (FIN) AF: 0.599 AC: 6315 AN: 10550

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41444 AN: 67932

Other (OTH) AF: 0.605 AC: 1275 AN: 2108

Alfa AF: 0.631 Hom.: 58996

Bravo AF: 0.684

Asia WGS AF: 0.626 AC: 2176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.66
PhyloP100		-1.2
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: rs2267443; hg19: chr22-42287454;