18-79410903-G-C

Variant names:

• chr18-79410903-G-C
• rs62096875
• NM_001278669.2:c.628G>C

Variant summary

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

The NM_001278669.2(NFATC1):​c.628G>C​(p.Val210Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,166 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V210M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NFATC1 NM_001278669.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.64
• Publications: 0 publications found

Genes affected

NFATC1 (HGNC:7775): (nuclear factor of activated T cells 1) The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes. [provided by RefSeq, Jul 2013]

NFATC1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278669.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	NM_001278669.2	MANE Select	c.628G>C	p.Val210Leu	missense	Exon 2 of 10	NP_001265598.1	O95644-1
	NFATC1	NM_172387.3		c.589G>C	p.Val197Leu	missense	Exon 2 of 10	NP_765975.1	O95644-6
	NFATC1	NM_006162.5		c.628G>C	p.Val210Leu	missense	Exon 2 of 10	NP_006153.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.628G>C	p.Val210Leu	missense	Exon 2 of 10	ENSP00000389377.2	O95644-1
	NFATC1	ENST00000329101.8	TSL:1	c.589G>C	p.Val197Leu	missense	Exon 2 of 10	ENSP00000327850.3	O95644-6
	NFATC1	ENST00000253506.9	TSL:1	c.628G>C	p.Val210Leu	missense	Exon 2 of 10	ENSP00000253506.5	O95644-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456166 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724268

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110760

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.23		Loss of glycosylation at S211 (P = 0.0897)
MVP		0.46
MPC		0.85
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.45
Mutation Taster		=6/94	disease causing

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: rs62096875; hg19: chr18-77170903;