2-203868865-T-C

Variant names:

• chr2-203868865-T-C
• rs231777
• NM_005214.5:c.109+814T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005214.5(CTLA4):​c.109+814T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 152,170 control chromosomes in the GnomAD database, including 53,168 homozygotes. 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 0.83 (53168 hom., cov: 31)
• Consequence: CTLA4 NM_005214.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 49 publications found

Genes affected

CTLA4 (HGNC:2505): (cytotoxic T-lymphocyte associated protein 4) This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]

CTLA4 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.109+814T>C		intron_variant	Intron 1 of 3	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.109+814T>C		intron_variant	Intron 1 of 2		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.109+814T>C		intron_variant	Intron 1 of 3		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126918 AN: 152052 Hom.: 53139 Cov.: 31

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.848

Gnomad OTH AF: 0.840

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.835 AC: 126990 AN: 152170 Hom.: 53168 Cov.: 31 AF XY: 0.837 AC XY: 62281 AN XY: 74400

African (AFR) AF: 0.774 AC: 32116 AN: 41498

American (AMR) AF: 0.868 AC: 13275 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2891 AN: 3472

East Asian (EAS) AF: 0.892 AC: 4622 AN: 5184

South Asian (SAS) AF: 0.934 AC: 4501 AN: 4818

European-Finnish (FIN) AF: 0.864 AC: 9147 AN: 10582

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.848 AC: 57640 AN: 67996

Other (OTH) AF: 0.841 AC: 1777 AN: 2114

Alfa AF: 0.839 Hom.: 8522

Bravo AF: 0.831

Asia WGS AF: 0.907 AC: 3152 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs231777; hg19: chr2-204733588;