chr12-57128476-C-G

Variant names:

• chr12-57128476-C-G
• rs35282763
• ENST00000556155.5:c.-22+497G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000556155.5(STAT6):​c.-22+497G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 355,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: STAT6 ENST00000556155.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.982
• Publications: 2 publications found

Genes affected

STAT6 (HGNC:11368): (signal transducer and activator of transcription 6) The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

LRP1 (HGNC:6692): (LDL receptor related protein 1) This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]

LRP1 Gene-Disease associations (from GenCC):

• keratosis follicularis spinulosa decalvans

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• atrophoderma vermiculata

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• developmental dysplasia of the hip 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• keratosis pilaris atrophicans

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BS2: High AC in GnomAd4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000556155.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1	NM_002332.3	MANE Select	c.-489C>G		upstream_gene	N/A	NP_002323.2	Q07954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT6	ENST00000556155.5	TSL:1	c.-22+497G>C		intron	N/A	ENSP00000451742.1	P42226-1
	STAT6	ENST00000553499.6	TSL:4	c.-22+3545G>C		intron	N/A	ENSP00000451074.2	P42226-1
	LRP1	ENST00000243077.8	TSL:1 MANE Select	c.-489C>G		upstream_gene	N/A	ENSP00000243077.3	Q07954-1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 35 AN: 150714 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.000487

GnomAD4 exome AF: 0.000118 AC: 24 AN: 204218 Hom.: 0 Cov.: 0 AF XY: 0.000154 AC XY: 16 AN XY: 103944

African (AFR) AF: 0.000501 AC: 3 AN: 5990

American (AMR) AF: 0.00 AC: 0 AN: 6044

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 12 AN: 7794

East Asian (EAS) AF: 0.000102 AC: 2 AN: 19602

South Asian (SAS) AF: 0.00 AC: 0 AN: 1814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1106

European-Non Finnish (NFE) AF: 0.0000378 AC: 5 AN: 132234

Other (OTH) AF: 0.000149 AC: 2 AN: 13430

GnomAD4 genome AF: 0.000232 AC: 35 AN: 150822 Hom.: 0 Cov.: 25 AF XY: 0.000244 AC XY: 18 AN XY: 73666

African (AFR) AF: 0.0000488 AC: 2 AN: 40998

American (AMR) AF: 0.000395 AC: 6 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67560

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000268

Asia WGS AF: 0.000291 AC: 1 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		0.98
PromoterAI		-0.16	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35282763; hg19: chr12-57522259;