NM_001366385.1:c.2399-4A>G

Variant names:

• chr17-80205031-A-G
• rs11653893
• NM_001366385.1:c.2399-4A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366385.1(CARD14):​c.2399-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,571,222 control chromosomes in the GnomAD database, including 180,221 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 Benign,association (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13255 hom., cov: 32)
  • Exomes 𝑓: 0.48 (166966 hom.)
• Consequence: CARD14 NM_001366385.1 splice_region, intron
• Scores: Splicing: ADA: 0.00003429
• Clinical Significance: Benign; association criteria provided, multiple submitters, no conflicts B:6 O:2
• Conservation: PhyloP100: -0.517

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:):

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-80205031-A-G is Benign according to our data. Variant chr17-80205031-A-G is described in ClinVar as [Benign, association]. Clinvar id is 402486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80205031-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.2399-4A>G		splice_region_variant, intron_variant	Intron 20 of 23	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.2399-4A>G		splice_region_variant, intron_variant	Intron 20 of 23		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61288 AN: 151884 Hom.: 13256 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.412 AC: 87216 AN: 211618 Hom.: 18785 AF XY: 0.420 AC XY: 48336 AN XY: 114984

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.481

Gnomad SAS exome AF: 0.341

Gnomad FIN exome AF: 0.420

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.439

GnomAD4 exome AF: 0.479 AC: 680308 AN: 1419220 Hom.: 166966 Cov.: 37 AF XY: 0.476 AC XY: 334090 AN XY: 701426

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.559

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.507

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.403 AC: 61288 AN: 152002 Hom.: 13255 Cov.: 32 AF XY: 0.399 AC XY: 29683 AN XY: 74308

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.407

Alfa AF: 0.444 Hom.: 5999

Bravo AF: 0.389

Asia WGS AF: 0.389 AC: 1352 AN: 3478

ClinVar

Significance: Benign; association

Submissions summary: Benign:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 51. Only high quality variants are reported. -

Pityriasis rubra pilaris Benign:1 Other:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: association

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CARD14 is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Potent mutations in Card14 have been shown to be associated with familial pustular psoriasis and other cutaneous inflammatory conditions like Pytriasis rubra pilaris. rs11653893 variant is associated with Psoriasis . However, more studies are required to ascertain the role of rs11653893 in Psoriasis -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Psoriasis 2 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.067
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs11653893; hg19: chr17-78178830;