rs5996080

Variant names:

• chr22-41893462-T-C
• rs5996080
• NM_004599.4:c.2377+177T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-41893462-T-C
• chr22-41893462-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004599.4(SREBF2):​c.2377+177T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,126 control chromosomes in the GnomAD database, including 2,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (2213 hom., cov: 32)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-41893462-T-C is Benign according to our data. Variant chr22-41893462-T-C is described in ClinVar as Benign. ClinVar VariationId is 1289993.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SREBF2	NM_004599.4	c.2377+177T>C		intron_variant	Intron 12 of 18	ENST00000361204.9	NP_004590.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SREBF2	ENST00000361204.9	c.2377+177T>C		intron_variant	Intron 12 of 18	1	NM_004599.4	ENSP00000354476.4
SREBF2	ENST00000424354.5	n.*422+177T>C		intron_variant	Intron 13 of 21	1		ENSP00000395728.1
SREBF2	ENST00000491541.1	n.928+177T>C		intron_variant	Intron 4 of 12	1
SREBF2	ENST00000710853.1	c.2287+177T>C		intron_variant	Intron 12 of 18			ENSP00000518526.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21264 AN: 152008 Hom.: 2205 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0840

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0729

Gnomad SAS AF: 0.0781

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0822

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.140 AC: 21306 AN: 152126 Hom.: 2213 Cov.: 32 AF XY: 0.137 AC XY: 10205 AN XY: 74374

African (AFR) AF: 0.298 AC: 12369 AN: 41448

American (AMR) AF: 0.0838 AC: 1280 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3470

East Asian (EAS) AF: 0.0732 AC: 380 AN: 5188

South Asian (SAS) AF: 0.0780 AC: 375 AN: 4810

European-Finnish (FIN) AF: 0.0774 AC: 821 AN: 10604

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0822 AC: 5588 AN: 68014

Other (OTH) AF: 0.111 AC: 234 AN: 2106

Alfa AF: 0.0899 Hom.: 1412

Bravo AF: 0.148

Asia WGS AF: 0.0920 AC: 318 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.92
DANN	Benign	0.75
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5996080; hg19: chr22-42289466;