chr2-203868127-A-G

Variant names:

• chr2-203868127-A-G
• rs231776
• NM_005214.5:c.109+76A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005214.5(CTLA4):​c.109+76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,180,210 control chromosomes in the GnomAD database, including 587,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74613 hom., cov: 32)
  • Exomes 𝑓: 1.0 (512790 hom.)
• Consequence: CTLA4 NM_005214.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.22
• Publications: 6 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 2-203868127-A-G is Benign according to our data. Variant chr2-203868127-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.109+76A>G		intron_variant	Intron 1 of 3	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.109+76A>G		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+76A>G		intron_variant	Intron 1 of 3		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes AF: 0.990 AC: 150636 AN: 152232 Hom.: 74556 Cov.: 32

Gnomad AFR AF: 0.963

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.995

GnomAD4 exome AF: 0.999 AC: 1026695 AN: 1027860 Hom.: 512790 AF XY: 0.999 AC XY: 528482 AN XY: 529006

African (AFR) AF: 0.961 AC: 23955 AN: 24916

American (AMR) AF: 0.999 AC: 41189 AN: 41248

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 22854 AN: 22854

East Asian (EAS) AF: 1.00 AC: 37458 AN: 37460

South Asian (SAS) AF: 1.00 AC: 75842 AN: 75844

European-Finnish (FIN) AF: 1.00 AC: 51362 AN: 51362

Middle Eastern (MID) AF: 0.999 AC: 4941 AN: 4944

European-Non Finnish (NFE) AF: 1.00 AC: 722795 AN: 722844

Other (OTH) AF: 0.998 AC: 46299 AN: 46388

GnomAD4 genome AF: 0.990 AC: 150752 AN: 152350 Hom.: 74613 Cov.: 32 AF XY: 0.990 AC XY: 73724 AN XY: 74498

African (AFR) AF: 0.963 AC: 40042 AN: 41572

American (AMR) AF: 0.997 AC: 15257 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68031 AN: 68040

Other (OTH) AF: 0.995 AC: 2106 AN: 2116

Alfa AF: 0.992 Hom.: 10676

Bravo AF: 0.988

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		2.2
PromoterAI		0.029	Neutral
Mutation Taster		=98/2	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: rs231776; hg19: chr2-204732850;