rs2228314

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004599.4(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 12639 hom., cov: 32)

Exomes 𝑓: 0.29 ( 67669 hom. )

Consequence

SREBF2
NM_004599.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.07

Publications

70 publications found

Variant links:

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

SREBF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SREBF2	NM_004599.4 link	c.1784G>C	p.Gly595Ala	missense_variant	Exon 10 of 19	ENST00000361204.9	NP_004590.2	Q12772-1A0A024R1Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SREBF2	ENST00000361204.9 link	c.1784G>C	p.Gly595Ala	missense_variant	Exon 10 of 19	1	NM_004599.4	ENSP00000354476.4	Q12772-1
SREBF2	ENST00000424354.5 link	n.1884G>C		non_coding_transcript_exon_variant	Exon 11 of 22	1		ENSP00000395728.1	G3V0I8
SREBF2	ENST00000710853.1 link	c.1694G>C	p.Gly565Ala	missense_variant	Exon 10 of 19			ENSP00000518526.1

Frequencies

GnomAD3 genomes

AF:

0.373

AC:

56625

AN:

151980

Hom.:

12602

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.342

AC:

85601

AN:

250568

AF XY:

0.326

show subpopulations

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 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.:

AF XY:

0.290

AC XY:

210883

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.590

AC:

19753

AN:

33478

American (AMR)

AF:

0.649

AC:

29014

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

9574

AN:

26134

East Asian (EAS)

AF:

0.266

AC:

10578

AN:

39698

South Asian (SAS)

AF:

0.357

AC:

30793

AN:

86252

European-Finnish (FIN)

AF:

0.218

AC:

11647

AN:

53410

Middle Eastern (MID)

AF:

0.349

AC:

2006

AN:

5742

European-Non Finnish (NFE)

AF:

0.263

AC:

292316

AN:

1111990

Other (OTH)

AF:

0.308

AC:

18584

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18923

37846

56768

75691

94614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10284

20568

30852

41136

51420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.373

AC:

56719

AN:

152100

Hom.:

12639

Cov.:

AF XY:

0.371

AC XY:

27588

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.584

AC:

24231

AN:

41460

American (AMR)

AF:

0.515

AC:

7876

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

1249

AN:

3470

East Asian (EAS)

AF:

0.205

AC:

1062

AN:

5170

South Asian (SAS)

AF:

0.361

AC:

1740

AN:

4822

European-Finnish (FIN)

AF:

0.196

AC:

2080

AN:

10586

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.255

AC:

17363

AN:

67984

Other (OTH)

AF:

0.353

AC:

747

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1667

3334

5002

6669

8336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.13

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.067

MetaRNN

Benign

0.000021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.49

PhyloP100

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

1.3

REVEL

Benign

0.043

Sift

Benign

0.87

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.082

MPC

0.18

ClinPred

0.00064

GERP RS

5.0

Varity_R

0.019

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over