chr17-80181466-G-C

Variant names:

• chr17-80181466-G-C
• rs758843053
• NM_001366385.1:c.28G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS2_Supporting

The NM_001366385.1(CARD14):​c.28G>C​(p.Ala10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,429,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A10T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.435

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06016594).
• 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.28G>C	p.Ala10Pro	missense_variant	Exon 5 of 24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.28G>C	p.Ala10Pro	missense_variant	Exon 5 of 24		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1429948 Hom.: 0 Cov.: 32 AF XY: 0.00000565 AC XY: 4 AN XY: 708438

African (AFR) AF: 0.00 AC: 0 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 40332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 37990

South Asian (SAS) AF: 0.00 AC: 0 AN: 81716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1095944

Other (OTH) AF: 0.0000169 AC: 1 AN: 59218

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 10 of the CARD14 protein (p.Ala10Pro). 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. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CARD14 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.12
DANN	Benign	0.89
DEOGEN2	Benign	0.081	T;T;T;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.66	.;.;.;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.060	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;L;L;.;L;L
PhyloP100		-0.43
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	.;.;.;.;.;N
REVEL	Benign	0.051
Sift	Benign	0.10	.;.;.;.;.;T
Sift4G	Benign	0.073	T;T;.;T;T;T
Polyphen		0.17	.;B;B;.;.;B
Vest4		0.10, 0.097
MutPred		0.14		Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);Gain of disorder (P = 0.0506);
MVP		0.62
MPC		0.37
ClinPred		0.089	T
GERP RS		-8.5
Varity_R		0.090
gMVP		0.52
Mutation Taster		=94/6	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

Publications

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Other links and lift over

dbSNP: rs758843053; hg19: chr17-78155265;