17-80184162-G-T

Variant names:

• chr17-80184162-G-T
• rs114688446
• NM_001366385.1:c.599G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366385.1(CARD14):​c.599G>T​(p.Ser200Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,563,976 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S200N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (10 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.279
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049067736).
• BP6: Variant 17-80184162-G-T is Benign according to our data. Variant chr17-80184162-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 458107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152274) while in subpopulation AFR AF = 0.0192 (797/41554). AF 95% confidence interval is 0.0181. There are 9 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 836 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.599G>T	p.Ser200Ile	missense	Exon 7 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.599G>T	p.Ser200Ile	missense	Exon 4 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.599G>T	p.Ser200Ile	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.599G>T	p.Ser200Ile	missense	Exon 7 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.599G>T	p.Ser200Ile	missense	Exon 4 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.599G>T	p.Ser200Ile	missense	Exon 4 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 833 AN: 152156 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00145 AC: 248 AN: 171110 AF XY: 0.00117

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000572

Gnomad OTH exome AF: 0.000859

GnomAD4 exome AF: 0.000551 AC: 778 AN: 1411702 Hom.: 10 Cov.: 31 AF XY: 0.000516 AC XY: 360 AN XY: 697448

African (AFR) AF: 0.0194 AC: 626 AN: 32332

American (AMR) AF: 0.00151 AC: 56 AN: 37022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25226

East Asian (EAS) AF: 0.00 AC: 0 AN: 36964

South Asian (SAS) AF: 0.0000375 AC: 3 AN: 79980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49580

Middle Eastern (MID) AF: 0.000886 AC: 5 AN: 5646

European-Non Finnish (NFE) AF: 0.0000147 AC: 16 AN: 1086426

Other (OTH) AF: 0.00123 AC: 72 AN: 58526

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152274 Hom.: 9 Cov.: 33 AF XY: 0.00514 AC XY: 383 AN XY: 74458

African (AFR) AF: 0.0192 AC: 797 AN: 41554

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.000145 Hom.: 3

Bravo AF: 0.00623

ESP6500AA AF: 0.0185 AC: 81

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00151 AC: 178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.4
DANN	Benign	0.96
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.28
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.023
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.020	D
Polyphen		0.74	P
Vest4		0.10
MVP		0.41
MPC		0.18
ClinPred		0.019	T
GERP RS		-3.7
Varity_R		0.095
gMVP		0.11
Mutation Taster		=98/2	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: rs114688446; hg19: chr17-78157961;