Genetic Variant NFATC2:c.*45-25_*45-19dupCCCCCCC (chr20-51391469-A-AGGGGGGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012340.5(NFATC2):c.*45-25_*45-19dupCCCCCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 948,130 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NFATC2
NM_012340.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0180

Variant links:

Genes affected

NFATC2 (HGNC:7776): (nuclear factor of activated T cells 2) This gene is a member of the nuclear factor of activated T cells (NFAT) family. The product of this gene is a DNA-binding protein with a REL-homology region (RHR) and an NFAT-homology region (NHR). This protein is present in the cytosol and only translocates to the nucleus upon T cell receptor (TCR) stimulation, where it becomes a member of the nuclear factors of activated T cells transcription complex. This complex plays a central role in inducing gene transcription during the immune response. Alternate transcriptional splice variants encoding different isoforms have been characterized. [provided by RefSeq, Apr 2012]

NFATC2 links:

LOC105372663 (HGNC:):

LOC105372663 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFATC2	NM_012340.5 link	c.45-25_45-19dupCCCCCCC		intron_variant	Intron 10 of 10	ENST00000371564.8	NP_036472.2	Q13469-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFATC2	ENST00000371564.8 link	c.45-19_45-18insCCCCCCC		intron_variant	Intron 10 of 10	1	NM_012340.5	ENSP00000360619.3		Q13469-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

140876

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

948130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

485072

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

20346

American (AMR)

AF:

0.00

AC:

AN:

38724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19954

East Asian (EAS)

AF:

0.00

AC:

AN:

32438

South Asian (SAS)

AF:

0.00

AC:

AN:

71352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3216

European-Non Finnish (NFE)

AF:

0.00000294

AC:

AN:

679214

Other (OTH)

AF:

0.00

AC:

AN:

40968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

140876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68036

African (AFR)

AF:

0.00

AC:

AN:

37230

American (AMR)

AF:

0.00

AC:

AN:

14030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00

AC:

AN:

4792

South Asian (SAS)

AF:

0.00

AC:

AN:

4262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65278

Other (OTH)

AF:

0.00

AC:

AN:

1918

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.018

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar for variant 20:51391469 A>AGGGGGGG . It may be empty.

20-51391469-AGGGG-AGGGGGGGGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over