NM_001366385.1:c.633G>A

Variant names:

• chr17-80184196-G-A
• rs4889990
• NM_001366385.1:c.633G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001366385.1(CARD14):​c.633G>A​(p.Glu211Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,554,468 control chromosomes in the GnomAD database, including 111,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.38 (11122 hom., cov: 33)
  • Exomes 𝑓: 0.38 (99952 hom.)
• Consequence: CARD14 NM_001366385.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.417
• Publications: 24 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]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-80184196-G-A is Benign according to our data. Variant chr17-80184196-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402483.
• BP7: Synonymous conserved (PhyloP=0.417 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 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.633G>A	p.Glu211Glu	synonymous	Exon 7 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.633G>A	p.Glu211Glu	synonymous	Exon 4 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.633G>A	p.Glu211Glu	synonymous	Exon 4 of 15	NP_001244899.1	Q9BXL6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.633G>A	p.Glu211Glu	synonymous	Exon 7 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.633G>A	p.Glu211Glu	synonymous	Exon 4 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.633G>A	p.Glu211Glu	synonymous	Exon 4 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57519 AN: 152016 Hom.: 11105 Cov.: 33

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.356 AC: 58858 AN: 165328 AF XY: 0.363

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.370

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.378

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.376 AC: 526613 AN: 1402334 Hom.: 99952 Cov.: 41 AF XY: 0.377 AC XY: 260820 AN XY: 691630

African (AFR) AF: 0.414 AC: 13314 AN: 32134

American (AMR) AF: 0.262 AC: 9586 AN: 36592

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9218 AN: 25068

East Asian (EAS) AF: 0.234 AC: 8592 AN: 36694

South Asian (SAS) AF: 0.435 AC: 34253 AN: 78810

European-Finnish (FIN) AF: 0.387 AC: 18878 AN: 48822

Middle Eastern (MID) AF: 0.419 AC: 2232 AN: 5332

European-Non Finnish (NFE) AF: 0.378 AC: 408807 AN: 1080768

Other (OTH) AF: 0.374 AC: 21733 AN: 58114

GnomAD4 genome AF: 0.378 AC: 57565 AN: 152134 Hom.: 11122 Cov.: 33 AF XY: 0.377 AC XY: 28048 AN XY: 74372

African (AFR) AF: 0.416 AC: 17288 AN: 41516

American (AMR) AF: 0.306 AC: 4682 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1279 AN: 3470

East Asian (EAS) AF: 0.209 AC: 1076 AN: 5154

South Asian (SAS) AF: 0.426 AC: 2055 AN: 4822

European-Finnish (FIN) AF: 0.375 AC: 3980 AN: 10600

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26003 AN: 67968

Other (OTH) AF: 0.368 AC: 779 AN: 2114

Alfa AF: 0.380 Hom.: 22891

Bravo AF: 0.371

Asia WGS AF: 0.320 AC: 1117 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.4
DANN	Benign	0.49
PhyloP100		0.42
Mutation Taster		=300/0	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: rs4889990; hg19: chr17-78157995; COSMIC: COSV60123736; COSMIC: COSV60123736;