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. The variant received -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
• Publications: 19 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]

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]

SGSH Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 3A

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 402486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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

GnomAD2 exomes AF: 0.412 AC: 87216 AN: 211618 AF XY: 0.420

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 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

African (AFR) AF: 0.242 AC: 7888 AN: 32540

American (AMR) AF: 0.275 AC: 11028 AN: 40166

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 10343 AN: 24398

East Asian (EAS) AF: 0.559 AC: 21402 AN: 38252

South Asian (SAS) AF: 0.343 AC: 28085 AN: 81844

European-Finnish (FIN) AF: 0.430 AC: 21902 AN: 50948

Middle Eastern (MID) AF: 0.395 AC: 1724 AN: 4360

European-Non Finnish (NFE) AF: 0.507 AC: 551494 AN: 1088390

Other (OTH) AF: 0.453 AC: 26442 AN: 58322

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

African (AFR) AF: 0.251 AC: 10409 AN: 41472

American (AMR) AF: 0.337 AC: 5147 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2628 AN: 5156

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4808

European-Finnish (FIN) AF: 0.430 AC: 4558 AN: 10588

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33926 AN: 67904

Other (OTH) AF: 0.407 AC: 859 AN: 2110

Alfa AF: 0.442 Hom.: 7092

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

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. -

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 -

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
AlphaMissense	Benign	0.063
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.067
DANN	Benign	0.54
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11653893; hg19: chr17-78178830;