22-37495769-T-G

Position:

• chr22-37495769-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000251973.10(CARD10):​c.2294A>C​(p.Asn765Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARD10 ENST00000251973.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

Genes affected

CARD10 (HGNC:16422): (caspase recruitment domain family member 10) The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antiparallel alpha helices. It participates in apoptosis signaling through highly specific protein-protein homophilic interactions. Like several other CARD proteins, CARD10 belongs to the membrane-associated guanylate kinase (MAGUK) family and activates NF-kappa-B (NFKB; see MIM 164011) through BCL10 (MIM 603517) (Wang et al., 2001 [PubMed 11259443]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD10	NM_014550.4	c.2294A>C	p.Asn765Thr	missense_variant	14/20	ENST00000251973.10	NP_055365.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD10	ENST00000251973.10	c.2294A>C	p.Asn765Thr	missense_variant	14/20	1	NM_014550.4	ENSP00000251973	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.2294A>C (p.N765T) alteration is located in exon 14 (coding exon 14) of the CARD10 gene. This alteration results from a A to C substitution at nucleotide position 2294, causing the asparagine (N) at amino acid position 765 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;D;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Uncertain	2.8	M;.;M;.
MutationTaster	Benign	0.56	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;.
Polyphen		1.0	D;.;D;.
Vest4		0.89
MutPred		0.42		Gain of phosphorylation at N765 (P = 0.0285);.;Gain of phosphorylation at N765 (P = 0.0285);.;
MVP		0.78
MPC		1.1
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs904865380; hg19: chr22-37891776;