rs2228314

Positions:

• chr22-41880738-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361204.9(SREBF2):​c.1784G>C​(p.Gly595Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,613,924 control chromosomes in the GnomAD database, including 80,308 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (12639 hom., cov: 32)
  • Exomes 𝑓: 0.29 (67669 hom.)
• Consequence: SREBF2 ENST00000361204.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1461386E-5).
• BP6: Variant 22-41880738-G-C is Benign according to our data. Variant chr22-41880738-G-C is described in ClinVar as [Benign]. Clinvar id is 1285913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SREBF2	NM_004599.4	c.1784G>C	p.Gly595Ala	missense_variant	10/19	ENST00000361204.9	NP_004590.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SREBF2	ENST00000361204.9	c.1784G>C	p.Gly595Ala	missense_variant	10/19	1	NM_004599.4	ENSP00000354476	P3
SREBF2	ENST00000424354.5	c.1884G>C	p.Arg628=	synonymous_variant, NMD_transcript_variant	11/22	1		ENSP00000395728
SREBF2	ENST00000710853.1	c.1694G>C	p.Gly565Ala	missense_variant	10/19			ENSP00000518526	A2

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56625 AN: 151980 Hom.: 12602 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.342 AC: 85601 AN: 250568 Hom.: 18269 AF XY: 0.326 AC XY: 44174 AN XY: 135568

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.665

Gnomad ASJ exome AF: 0.370

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.354

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.290 AC: 424265 AN: 1461824 Hom.: 67669 Cov.: 53 AF XY: 0.290 AC XY: 210883 AN XY: 727202

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.649

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.263

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.373 AC: 56719 AN: 152100 Hom.: 12639 Cov.: 32 AF XY: 0.371 AC XY: 27588 AN XY: 74354

Gnomad4 AFR AF: 0.584

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.360

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.353

Alfa AF: 0.285 Hom.: 5169

Bravo AF: 0.409

TwinsUK AF: 0.274 AC: 1015

ALSPAC AF: 0.272 AC: 1047

ESP6500AA AF: 0.571 AC: 2515

ESP6500EA AF: 0.266 AC: 2288

ExAC AF: 0.333 AC: 40453

Asia WGS AF: 0.317 AC: 1103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 22182810, 19740467, 12801623, 12119189, 28902428) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.067	T
MetaRNN	Benign	0.000021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.49	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.043
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.082
MPC		0.18
ClinPred		0.00064	T
GERP RS		5.0
Varity_R		0.019
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228314; hg19: chr22-42276742; COSMIC: COSV63330828; COSMIC: COSV63330828;