17-80190856-C-T

Variant names:

• chr17-80190856-C-T
• rs770212092
• NM_001366385.1:c.1046C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BS1_Supporting BS2_Supporting

The NM_001366385.1(CARD14):​c.1046C>T​(p.Ala349Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A349E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.44
• Publications: 1 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: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• psoriasis 2

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12021601).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000329 (5/152122) while in subpopulation AMR AF = 0.000262 (4/15266). AF 95% confidence interval is 0.0000888. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1046C>T	p.Ala349Val	missense	Exon 10 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.1046C>T	p.Ala349Val	missense	Exon 7 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.1046C>T	p.Ala349Val	missense	Exon 7 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.1046C>T	p.Ala349Val	missense	Exon 10 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.1046C>T	p.Ala349Val	missense	Exon 7 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.1046C>T	p.Ala349Val	missense	Exon 7 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251244 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.000262 AC: 4 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.082
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.035	D
Polyphen		0.69	P
Vest4		0.18
MutPred		0.43		Gain of methylation at K346 (P = 0.1061)
MVP		0.74
MPC		0.21
ClinPred		0.13	T
GERP RS		2.2
Varity_R		0.043
gMVP		0.20
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770212092; hg19: chr17-78164655; COSMIC: COSV60125055; COSMIC: COSV60125055;