22-41868265-G-T

Variant names:

• chr22-41868265-G-T
• rs2269657
• NM_004599.4:c.539-346G>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.539-346G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,976 control chromosomes in the GnomAD database, including 12,413 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 0.37 (12413 hom., cov: 32)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 11 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SREBF2	NM_004599.4	c.539-346G>T		intron_variant	Intron 2 of 18	ENST00000361204.9	NP_004590.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SREBF2	ENST00000361204.9	c.539-346G>T		intron_variant	Intron 2 of 18	1	NM_004599.4	ENSP00000354476.4
SREBF2	ENST00000424354.5	n.539-346G>T		intron_variant	Intron 2 of 21	1		ENSP00000395728.1
SREBF2	ENST00000710853.1	c.449-346G>T		intron_variant	Intron 2 of 18			ENSP00000518526.1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56234 AN: 151858 Hom.: 12372 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.371 AC: 56335 AN: 151976 Hom.: 12413 Cov.: 32 AF XY: 0.369 AC XY: 27449 AN XY: 74294

African (AFR) AF: 0.575 AC: 23793 AN: 41396

American (AMR) AF: 0.513 AC: 7828 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1270 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1202 AN: 5168

South Asian (SAS) AF: 0.362 AC: 1741 AN: 4810

European-Finnish (FIN) AF: 0.196 AC: 2080 AN: 10594

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17309 AN: 67964

Other (OTH) AF: 0.351 AC: 741 AN: 2114

Alfa AF: 0.263 Hom.: 2630

Bravo AF: 0.407

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.012
DANN	Benign	0.63
PhyloP100		-2.6
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: rs2269657; hg19: chr22-42264269;