22-41867108-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004599.4(SREBF2):c.366C>A(p.Pro122=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,614,200 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (84 hom.)
• Consequence: SREBF2 NM_004599.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.527

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 22-41867108-C-A is Benign according to our data. Variant chr22-41867108-C-A is described in ClinVar as [Benign]. Clinvar id is 785688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.527 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF2	NM_004599.4	c.366C>A	p.Pro122=	synonymous_variant	2/19	ENST00000361204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF2	ENST00000361204.9	c.366C>A	p.Pro122=	synonymous_variant	2/19	1	NM_004599.4	P3
SREBF2	ENST00000424354.5	c.366C>A	p.Pro122=	synonymous_variant, NMD_transcript_variant	2/22	1
SREBF2	ENST00000710853.1	c.276C>A	p.Pro92=	synonymous_variant	2/19			A2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2684 AN: 152188 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00456 AC: 1145 AN: 251316 Hom.: 36 AF XY: 0.00318 AC XY: 432 AN XY: 135854

Gnomad AFR exome AF: 0.0640

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00174 AC: 2542 AN: 1461894 Hom.: 84 Cov.: 32 AF XY: 0.00148 AC XY: 1077 AN XY: 727248

Gnomad4 AFR exome AF: 0.0631

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0177 AC: 2690 AN: 152306 Hom.: 76 Cov.: 32 AF XY: 0.0164 AC XY: 1222 AN XY: 74476

Gnomad4 AFR AF: 0.0610

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00782 Hom.: 18

Bravo AF: 0.0204

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	5.9
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2229438; hg19: chr22-42263112;