18-79486406-T-G

Variant names:

• chr18-79486406-T-G
• rs754093
• NM_001278669.2:c.2251T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278669.2(NFATC1):​c.2251T>G​(p.Cys751Gly) variant causes a missense change. The variant allele was found at a frequency of 0.438 in 1,612,454 control chromosomes in the GnomAD database, including 158,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (12087 hom., cov: 33)
  • Exomes 𝑓: 0.44 (146215 hom.)
• Consequence: NFATC1 NM_001278669.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.90
• Publications: 44 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010785162).
• BP6: Variant 18-79486406-T-G is Benign according to our data. Variant chr18-79486406-T-G is described in ClinVar as Benign. ClinVar VariationId is 1640667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFATC1	NM_001278669.2	c.2251T>G	p.Cys751Gly	missense_variant	Exon 9 of 10	ENST00000427363.7	NP_001265598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFATC1	ENST00000427363.7	c.2251T>G	p.Cys751Gly	missense_variant	Exon 9 of 10	1	NM_001278669.2	ENSP00000389377.2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57478 AN: 151872 Hom.: 12095 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.424 AC: 106033 AN: 250046 AF XY: 0.432

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.444 AC: 647999 AN: 1460464 Hom.: 146215 Cov.: 76 AF XY: 0.445 AC XY: 323042 AN XY: 726536

African (AFR) AF: 0.181 AC: 6074 AN: 33478

American (AMR) AF: 0.407 AC: 18218 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 12989 AN: 26122

East Asian (EAS) AF: 0.376 AC: 14929 AN: 39696

South Asian (SAS) AF: 0.397 AC: 34256 AN: 86250

European-Finnish (FIN) AF: 0.476 AC: 24835 AN: 52124

Middle Eastern (MID) AF: 0.557 AC: 3209 AN: 5766

European-Non Finnish (NFE) AF: 0.456 AC: 507334 AN: 1111934

Other (OTH) AF: 0.433 AC: 26155 AN: 60376

GnomAD4 genome AF: 0.378 AC: 57472 AN: 151990 Hom.: 12087 Cov.: 33 AF XY: 0.383 AC XY: 28420 AN XY: 74274

African (AFR) AF: 0.182 AC: 7541 AN: 41482

American (AMR) AF: 0.443 AC: 6780 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1697 AN: 3470

East Asian (EAS) AF: 0.356 AC: 1828 AN: 5132

South Asian (SAS) AF: 0.381 AC: 1838 AN: 4820

European-Finnish (FIN) AF: 0.475 AC: 5016 AN: 10556

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31376 AN: 67918

Other (OTH) AF: 0.429 AC: 905 AN: 2112

Alfa AF: 0.432 Hom.: 31404

Bravo AF: 0.369

TwinsUK AF: 0.463 AC: 1715

ALSPAC AF: 0.456 AC: 1758

ESP6500AA AF: 0.183 AC: 808

ESP6500EA AF: 0.463 AC: 3984

ExAC AF: 0.415 AC: 50385

Asia WGS AF: 0.340 AC: 1184 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.487

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Benign	0.0	.;.;D;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.47	T;T;T;T;T;T
MetaRNN	Benign	0.0011	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M;.;M;.;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.1	D;D;.;D;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;D;.;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Vest4		0.35
ClinPred		0.067	T
GERP RS		3.5
Varity_R		0.72
gMVP		0.42
Mutation Taster		=95/5	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: rs754093; hg19: chr18-77246406; COSMIC: COSV53701053;