chr17-80205153-G-C

Variant names:

• chr17-80205153-G-C
• rs950950885
• NM_001366385.1:c.2517G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001366385.1(CARD14):​c.2517G>C​(p.Lys839Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.86
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24176523).
• BS2: High AC in GnomAdExome4 at 5 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 rank	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.2517G>C	p.Lys839Asn	missense_variant	Exon 21 of 24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.2517G>C	p.Lys839Asn	missense_variant	Exon 21 of 24		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461508 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.0000663 AC: 4 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000483 AC: 2 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1

Mar 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 839 of the CARD14 protein (p.Lys839Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CARD14-related conditions. ClinVar contains an entry for this variant (Variation ID: 576948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CARD14 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autoinflammatory syndrome Uncertain:1

Dec 20, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;T
Eigen	Benign	0.099
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M;M
PhyloP100		1.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	.;.;N
REVEL	Benign	0.099
Sift	Uncertain	0.0060	.;.;D
Sift4G	Uncertain	0.014	D;.;D
Polyphen		0.74	P;P;P
Vest4		0.32
MutPred		0.53		Loss of ubiquitination at K839 (P = 0.0297);Loss of ubiquitination at K839 (P = 0.0297);Loss of ubiquitination at K839 (P = 0.0297);
MVP		0.70
MPC		0.50
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.21
gMVP		0.64
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs950950885; hg19: chr17-78178952;