Genetic Variant NM_005214.5:c.*1190C>T (chr2-203874002-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005214.5(CTLA4):c.*1190C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 201,390 control chromosomes in the GnomAD database, including 98,978 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 0.99 ( 74524 hom., cov: 32)

Exomes 𝑓: 1.0 ( 24454 hom. )

Consequence

CTLA4
NM_005214.5 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00100

Publications

10 publications found

Variant links:

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

CTLA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) 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 link	c.*1190C>T		downstream_gene_variant		ENST00000648405.2	NP_005205.2	P16410-1
CTLA4	NM_001037631.3 link	c.*1227C>T		downstream_gene_variant			NP_001032720.1	P16410-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2 link	c.*1190C>T		downstream_gene_variant			NM_005214.5	ENSP00000497102.1		P16410-1
CTLA4	ENST00000696479.1 link	c.*1190C>T		downstream_gene_variant				ENSP00000512655.1		A0A8Q3SIR7

Frequencies

GnomAD3 genomes

AF:

0.989

AC:

150530

AN:

152204

Hom.:

74467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.961

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:

0.994

GnomAD4 exome

AF:

0.998

AC:

48986

AN:

49068

Hom.:

24454

Cov.:

AF XY:

0.999

AC XY:

22723

AN XY:

22754

show subpopulations

African (AFR)

AF:

0.966

AC:

1880

AN:

1946

American (AMR)

AF:

0.997

AC:

1354

AN:

1358

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3168

AN:

3168

East Asian (EAS)

AF:

1.00

AC:

8006

AN:

8008

South Asian (SAS)

AF:

1.00

AC:

440

AN:

440

European-Finnish (FIN)

AF:

1.00

AC:

464

AN:

464

Middle Eastern (MID)

AF:

1.00

AC:

296

AN:

296

European-Non Finnish (NFE)

AF:

1.00

AC:

29320

AN:

29322

Other (OTH)

AF:

0.998

AC:

4058

AN:

4066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.989

AC:

150646

AN:

152322

Hom.:

74524

Cov.:

AF XY:

0.989

AC XY:

73666

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.961

AC:

39958

AN:

41566

American (AMR)

AF:

0.997

AC:

15251

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5186

AN:

5188

South Asian (SAS)

AF:

1.00

AC:

4816

AN:

4818

European-Finnish (FIN)

AF:

1.00

AC:

10622

AN:

10622

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68035

AN:

68040

Other (OTH)

AF:

0.994

AC:

2100

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.992

Hom.:

10647

Bravo

AF:

0.987

Asia WGS

AF:

1.00

AC:

3477

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.7

(source)

DANN

Benign

0.63

PhyloP100

0.0010

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over