NM_001366385.1:c.1772C>G

Variant names:

• chr17-80198512-C-G
• rs200102454
• NM_001366385.1:c.1772C>G

Variant summary

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

The NM_001366385.1(CARD14):​c.1772C>G​(p.Thr591Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,120 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. T591M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• Publications: 8 publications found

Genes affected

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

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_001366385.1. 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
	CARD14	NM_001366385.1	MANE Select	c.1772C>G	p.Thr591Arg	missense	Exon 16 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.1772C>G	p.Thr591Arg	missense	Exon 13 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.1772C>G	p.Thr591Arg	missense	Exon 13 of 15	NP_001244899.1	Q9BXL6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.1772C>G	p.Thr591Arg	missense	Exon 16 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.1772C>G	p.Thr591Arg	missense	Exon 13 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.1772C>G	p.Thr591Arg	missense	Exon 13 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726760

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.48		Gain of methylation at T591 (P = 0.0455)
MVP		0.77
MPC		0.69
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.64
Mutation Taster		=29/71	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: rs200102454; hg19: chr17-78172311;