rs146214639

Variant names:

• chr17-80184012-T-G
• rs146214639
• NM_001366385.1:c.449T>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001366385.1(CARD14):​c.449T>G​(p.Leu150Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,587,026 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L150L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 0.182
• Publications: 6 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001366385.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.009278655).
• BP6: Variant 17-80184012-T-G is Benign according to our data. Variant chr17-80184012-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68781.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.001 (152/151872) while in subpopulation NFE AF = 0.00184 (125/67914). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 152 AD gene.

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.449T>G	p.Leu150Arg	missense	Exon 7 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.449T>G	p.Leu150Arg	missense	Exon 4 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.449T>G	p.Leu150Arg	missense	Exon 4 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.449T>G	p.Leu150Arg	missense	Exon 7 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.449T>G	p.Leu150Arg	missense	Exon 4 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.449T>G	p.Leu150Arg	missense	Exon 4 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 152 AN: 151752 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00106 AC: 227 AN: 213974 AF XY: 0.00107

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000772

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000166

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00211 AC: 3021 AN: 1435154 Hom.: 7 Cov.: 31 AF XY: 0.00203 AC XY: 1443 AN XY: 710568

African (AFR) AF: 0.000363 AC: 12 AN: 33068

American (AMR) AF: 0.000754 AC: 31 AN: 41138

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 38754

South Asian (SAS) AF: 0.00 AC: 0 AN: 82628

European-Finnish (FIN) AF: 0.000331 AC: 17 AN: 51396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00257 AC: 2820 AN: 1097830

Other (OTH) AF: 0.00236 AC: 140 AN: 59278

GnomAD4 genome AF: 0.00100 AC: 152 AN: 151872 Hom.: 0 Cov.: 33 AF XY: 0.000956 AC XY: 71 AN XY: 74250

African (AFR) AF: 0.000362 AC: 15 AN: 41390

American (AMR) AF: 0.000655 AC: 10 AN: 15272

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

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00107

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00104 AC: 126

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Pityriasis rubra pilaris;C1864497:Psoriasis 2 (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	CARD14-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.18
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.069
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.89	P
Vest4		0.22
MVP		0.73
MPC		0.24
ClinPred		0.041	T
GERP RS		-2.8
Varity_R		0.30
gMVP		0.49
Mutation Taster		=90/10	polymorphism

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: rs146214639; hg19: chr17-78157811;