17-80205209-T-C

Position:

• chr17-80205209-T-C

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.2569+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,608,286 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: CARD14 NM_001366385.1 splice_region, intron
• Scores: Splicing: ADA: 0.00007751
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.84

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]

ENSG00000262580 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-80205209-T-C is Benign according to our data. Variant chr17-80205209-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 527886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80205209-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00184 (280/152234) while in subpopulation NFE AF= 0.00325 (221/67986). AF 95% confidence interval is 0.0029. There are 2 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 280 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.2569+4T>C		splice_region_variant, intron_variant		ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.2569+4T>C		splice_region_variant, intron_variant			NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00176 AC: 435 AN: 246506 Hom.: 2 AF XY: 0.00196 AC XY: 262 AN XY: 133412

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000675

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00103

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00266 AC: 3876 AN: 1456052 Hom.: 8 Cov.: 35 AF XY: 0.00266 AC XY: 1924 AN XY: 723682

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000948

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.000699

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00165 AC XY: 123 AN XY: 74438

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00186

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	CARD14: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0030
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.0020
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: rs146678380; hg19: chr17-78179008; COSMIC: COSV58340739; COSMIC: COSV58340739;