rs2228314

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000361204.9(SREBF2):ā€‹c.1784G>Cā€‹(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 (ā˜…ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: š‘“ 0.37 ( 12639 hom., cov: 32)
Exomes š‘“: 0.29 ( 67669 hom. )

Consequence

SREBF2
ENST00000361204.9 missense

Scores

18

Clinical Significance

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

Conservation

PhyloP100: 1.07
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]

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ACMG classification

Classification made for transcript

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
SREBF2NM_004599.4 linkuse as main transcriptc.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
SREBF2ENST00000361204.9 linkuse as main transcriptc.1784G>C p.Gly595Ala missense_variant 10/191 NM_004599.4 ENSP00000354476 P3Q12772-1
SREBF2ENST00000424354.5 linkuse as main transcriptc.1884G>C p.Arg628= synonymous_variant, NMD_transcript_variant 11/221 ENSP00000395728
SREBF2ENST00000710853.1 linkuse as main transcriptc.1694G>C p.Gly565Ala missense_variant 10/19 ENSP00000518526 A2

Frequencies

GnomAD3 genomes
AF:
0.373
AC:
56625
AN:
151980
Hom.:
12602
Cov.:
32
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
GnomAD3 exomes
AF:
0.342
AC:
85601
AN:
250568
Hom.:
18269
AF XY:
0.326
AC XY:
44174
AN XY:
135568
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 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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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