17-80188528-C-G

Variant names:

• chr17-80188528-C-G
• rs149318654
• NM_001366385.1:c.827C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366385.1(CARD14):​c.827C>G​(p.Ser276Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,364,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S276L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87
• Publications: 6 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• psoriasis 2

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39635524).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	NM_001366385.1	MANE Select	c.827C>G	p.Ser276Trp	missense	Exon 8 of 24	NP_001353314.1
	CARD14	NM_024110.4		c.827C>G	p.Ser276Trp	missense	Exon 5 of 21	NP_077015.2
	CARD14	NM_001257970.1		c.827C>G	p.Ser276Trp	missense	Exon 5 of 15	NP_001244899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.827C>G	p.Ser276Trp	missense	Exon 8 of 24	ENSP00000498071.1
	CARD14	ENST00000344227.6	TSL:1	c.827C>G	p.Ser276Trp	missense	Exon 5 of 21	ENSP00000344549.2
	CARD14	ENST00000570421.5	TSL:1	c.827C>G	p.Ser276Trp	missense	Exon 5 of 15	ENSP00000461806.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1364890 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 671574

African (AFR) AF: 0.00 AC: 0 AN: 29778

American (AMR) AF: 0.00 AC: 0 AN: 31568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21372

East Asian (EAS) AF: 0.00 AC: 0 AN: 35398

South Asian (SAS) AF: 0.00 AC: 0 AN: 71560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4774

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1063398

Other (OTH) AF: 0.00 AC: 0 AN: 56172

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoinflammatory syndrome Uncertain:1

Jun 15, 2017

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.36		Gain of catalytic residue at L274 (P = 0.004)
MVP		0.85
MPC		0.76
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.33
gMVP		0.31

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: rs149318654; hg19: chr17-78162327;