17-80205094-C-T

Variant names:

• chr17-80205094-C-T
• rs11652075
• NM_001366385.1:c.2458C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001366385.1(CARD14):​c.2458C>T​(p.Arg820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,612,294 control chromosomes in the GnomAD database, including 183,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13113 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170694 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:8 O:1
• Conservation: PhyloP100: 2.56
• Publications: 113 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, ClinGen, Myriad Women’s Health, PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8051267E-4).
• BP6: Variant 17-80205094-C-T is Benign according to our data. Variant chr17-80205094-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402487.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	NM_001366385.1	MANE Select	c.2458C>T	p.Arg820Trp	missense	Exon 21 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.2458C>T	p.Arg820Trp	missense	Exon 18 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NR_047566.2		n.2595C>T		non_coding_transcript_exon	Exon 19 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.2458C>T	p.Arg820Trp	missense	Exon 21 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.2458C>T	p.Arg820Trp	missense	Exon 18 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000651672.1		c.2485C>T	p.Arg829Trp	missense	Exon 20 of 23	ENSP00000499145.1	A0A494C1N2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60778 AN: 151996 Hom.: 13115 Cov.: 33

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.402

GnomAD2 exomes AF: 0.414 AC: 102372 AN: 247554 AF XY: 0.421

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.477 AC: 697129 AN: 1460180 Hom.: 170694 Cov.: 46 AF XY: 0.474 AC XY: 344601 AN XY: 726394

African (AFR) AF: 0.232 AC: 7759 AN: 33464

American (AMR) AF: 0.273 AC: 12165 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10994 AN: 26078

East Asian (EAS) AF: 0.547 AC: 21677 AN: 39664

South Asian (SAS) AF: 0.342 AC: 29508 AN: 86188

European-Finnish (FIN) AF: 0.431 AC: 22804 AN: 52934

Middle Eastern (MID) AF: 0.405 AC: 2289 AN: 5648

European-Non Finnish (NFE) AF: 0.506 AC: 562704 AN: 1111302

Other (OTH) AF: 0.451 AC: 27229 AN: 60318

GnomAD4 genome AF: 0.400 AC: 60777 AN: 152114 Hom.: 13113 Cov.: 33 AF XY: 0.395 AC XY: 29401 AN XY: 74358

African (AFR) AF: 0.241 AC: 9997 AN: 41502

American (AMR) AF: 0.335 AC: 5115 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1433 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2555 AN: 5160

South Asian (SAS) AF: 0.331 AC: 1600 AN: 4830

European-Finnish (FIN) AF: 0.430 AC: 4559 AN: 10590

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.499 AC: 33915 AN: 67958

Other (OTH) AF: 0.402 AC: 849 AN: 2112

Alfa AF: 0.468 Hom.: 74057

Bravo AF: 0.385

TwinsUK AF: 0.504 AC: 1867

ALSPAC AF: 0.519 AC: 2001

ESP6500AA AF: 0.249 AC: 1095

ESP6500EA AF: 0.492 AC: 4227

ExAC AF: 0.414 AC: 50234

Asia WGS AF: 0.383 AC: 1333 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
1	-	1	Pityriasis rubra pilaris (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)
-	-	1	Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.6
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.035	D
Polyphen		0.91	P
Vest4		0.11
MPC		0.37
ClinPred		0.028	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.073
gMVP		0.69
Mutation Taster		=96/4	polymorphism (auto)

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: rs11652075; hg19: chr17-78178893; COSMIC: COSV106424640; COSMIC: COSV106424640;