rs139274935

Positions:

• chr17-80198399-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_001366385.1(CARD14):​c.1659C>T​(p.Ser553=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,597,498 control chromosomes in the GnomAD database, including 2 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 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (2 hom.)
• Consequence: CARD14 NM_001366385.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.0009650
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.22

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-80198399-C-T is Benign according to our data. Variant chr17-80198399-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 527881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000368 (56/152340) while in subpopulation EAS AF= 0.00058 (3/5174). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 56 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.1659C>T	p.Ser553=	splice_region_variant, synonymous_variant	16/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.1659C>T	p.Ser553=	splice_region_variant, synonymous_variant	16/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000490 AC: 118 AN: 240834 Hom.: 0 AF XY: 0.000460 AC XY: 60 AN XY: 130486

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.000589

Gnomad ASJ exome AF: 0.00375

Gnomad EAS exome AF: 0.000715

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000683

GnomAD4 exome AF: 0.000542 AC: 783 AN: 1445158 Hom.: 2 Cov.: 31 AF XY: 0.000533 AC XY: 382 AN XY: 716342

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000544

Gnomad4 ASJ exome AF: 0.00388

Gnomad4 EAS exome AF: 0.000508

Gnomad4 SAS exome AF: 0.000249

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000534

Gnomad4 OTH exome AF: 0.000486

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000715 Hom.: 0

Bravo AF: 0.000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

CARD14: BP4, BP7 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00097
dbscSNV1_RF	Benign	0.15
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: rs139274935; hg19: chr17-78172198; COSMIC: COSV99061899; COSMIC: COSV99061899;