rs115582620

chr17-80181623-G-Achr17-80181623-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366385.1(CARD14):c.185G>A(p.Arg62Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,552,610 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (12 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.32

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036271214).
• BP6: Variant 17-80181623-G-A is Benign according to our data. Variant chr17-80181623-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 68777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80181623-G-A is described in Lovd as [Pathogenic]. Variant chr17-80181623-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00423 (644/152316) while in subpopulation AFR AF= 0.0143 (596/41564). AF 95% confidence interval is 0.0134. There are 4 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 635 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.185G>A	p.Arg62Gln	missense_variant	5/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.185G>A	p.Arg62Gln	missense_variant	5/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 635 AN: 152198 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00138 AC: 212 AN: 153392 Hom.: 0 AF XY: 0.00101 AC XY: 82 AN XY: 81550

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000516

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000851 AC: 1191 AN: 1400294 Hom.: 12 Cov.: 32 AF XY: 0.000763 AC XY: 527 AN XY: 691092

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0150

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.00423 AC: 644 AN: 152316 Hom.: 4 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74488

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.00491

ESP6500AA AF: 0.0128 AC: 55

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000991 AC: 105

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CARD14: BP4, BS1, BS2 -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2021

- -

CARD14-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	11
Dann	Benign	0.91
DEOGEN2	Benign	0.0066	T;T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.26	N
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.46	T;.;T;T;T
Polyphen		0.0010	B;B;.;.;B
Vest4		0.13
MVP		0.39
MPC		0.18
ClinPred		0.0063	T
GERP RS		-2.7
Varity_R		0.025
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs115582620; hg19: chr17-78155422; COSMIC: COSV100712589; COSMIC: COSV100712589;