9-93110571-C-T

Position:

• chr9-93110571-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032310.5(CARD19):​c.154C>T​(p.Arg52Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,445,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CARD19 NM_032310.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

Genes affected

CARD19 (HGNC:28148): (caspase recruitment domain family member 19) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD19	NM_032310.5	c.154C>T	p.Arg52Trp	missense_variant	3/6	ENST00000375464.7	NP_115686.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD19	ENST00000375464.7	c.154C>T	p.Arg52Trp	missense_variant	3/6	1	NM_032310.5	ENSP00000364613	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 241492 Hom.: 0 AF XY: 0.0000308 AC XY: 4 AN XY: 130008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000350

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1445250 Hom.: 0 Cov.: 34 AF XY: 0.0000140 AC XY: 10 AN XY: 716612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 22, 2021

The c.154C>T (p.R52W) alteration is located in exon 3 (coding exon 3) of the CARD19 gene. This alteration results from a C to T substitution at nucleotide position 154, causing the arginine (R) at amino acid position 52 to be replaced by a tryptophan (W). 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	Pathogenic	0.94
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.67		Loss of disorder (P = 0.0172);
MVP		0.50
MPC		0.35
ClinPred		0.78	D
GERP RS		3.8
gMVP		0.65

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: rs909678259; hg19: chr9-95872853; COSMIC: COSV64935845;