rs6013193

Variant names:

• chr20-51475490-T-G
• rs6013193
• NM_012340.5:c.1503A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_012340.5(NFATC2):​c.1503A>C​(p.Ile501Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,613,548 control chromosomes in the GnomAD database, including 188,046 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 0.53 (23004 hom., cov: 30)
  • Exomes 𝑓: 0.47 (165042 hom.)
• Consequence: NFATC2 NM_012340.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• joint contractures, osteochondromas, and B-cell lymphoma

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012340.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC2	NM_012340.5	MANE Select	c.1503A>C	p.Ile501Ile	synonymous	Exon 4 of 11	NP_036472.2
	NFATC2	NM_173091.4		c.1503A>C	p.Ile501Ile	synonymous	Exon 4 of 10	NP_775114.1
	NFATC2	NM_001258292.2		c.1443A>C	p.Ile481Ile	synonymous	Exon 4 of 10	NP_001245221.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC2	ENST00000371564.8	TSL:1 MANE Select	c.1503A>C	p.Ile501Ile	synonymous	Exon 4 of 11	ENSP00000360619.3
	NFATC2	ENST00000396009.7	TSL:1	c.1503A>C	p.Ile501Ile	synonymous	Exon 4 of 10	ENSP00000379330.3
	NFATC2	ENST00000609943.5	TSL:1	c.1443A>C	p.Ile481Ile	synonymous	Exon 4 of 10	ENSP00000477370.1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80787 AN: 151696 Hom.: 22955 Cov.: 30

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.532

GnomAD2 exomes AF: 0.471 AC: 118513 AN: 251466 AF XY: 0.465

Gnomad AFR exome AF: 0.747

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.566

Gnomad EAS exome AF: 0.377

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.471 AC: 688940 AN: 1461734 Hom.: 165042 Cov.: 61 AF XY: 0.470 AC XY: 341768 AN XY: 727174

African (AFR) AF: 0.752 AC: 25170 AN: 33476

American (AMR) AF: 0.518 AC: 23156 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14864 AN: 26132

East Asian (EAS) AF: 0.369 AC: 14651 AN: 39696

South Asian (SAS) AF: 0.434 AC: 37468 AN: 86254

European-Finnish (FIN) AF: 0.329 AC: 17585 AN: 53420

Middle Eastern (MID) AF: 0.566 AC: 3229 AN: 5700

European-Non Finnish (NFE) AF: 0.471 AC: 523265 AN: 1111950

Other (OTH) AF: 0.489 AC: 29552 AN: 60384

GnomAD4 genome AF: 0.533 AC: 80884 AN: 151814 Hom.: 23004 Cov.: 30 AF XY: 0.524 AC XY: 38871 AN XY: 74184

African (AFR) AF: 0.741 AC: 30640 AN: 41366

American (AMR) AF: 0.498 AC: 7595 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3468

East Asian (EAS) AF: 0.370 AC: 1905 AN: 5146

South Asian (SAS) AF: 0.428 AC: 2053 AN: 4796

European-Finnish (FIN) AF: 0.337 AC: 3549 AN: 10532

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31572 AN: 67938

Other (OTH) AF: 0.530 AC: 1116 AN: 2106

Alfa AF: 0.509 Hom.: 11244

Bravo AF: 0.557

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.4
DANN	Benign	0.74
PhyloP100		0.13
Mutation Taster		=99/1	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: rs6013193; hg19: chr20-50092027; COSMIC: COSV65356048;