5-40843457-G-A

Position:

• chr5-40843457-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032587.4(CARD6):​c.589G>A​(p.Gly197Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CARD6 NM_032587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

CARD6 (HGNC:16394): (caspase recruitment domain family member 6) This gene encodes a protein that contains a caspase recruitment domain (CARD), an antiparallel six-helical bundle that mediates homotypic protein-protein interactions. The encoded protein is a microtubule-associated protein that has been shown to interact with receptor-interacting protein kinases and positively modulate signal transduction pathways converging on activation of the inducible transcription factor NF-kB. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1877842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD6	NM_032587.4	c.589G>A	p.Gly197Arg	missense_variant	2/3	ENST00000254691.10	NP_115976.2
CARD6	XM_017009989.2	c.283+1792G>A		intron_variant			XP_016865478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD6	ENST00000254691.10	c.589G>A	p.Gly197Arg	missense_variant	2/3	1	NM_032587.4	ENSP00000254691.5
CARD6	ENST00000381677.4	c.589G>A	p.Gly197Arg	missense_variant	2/3	1		ENSP00000371093.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726896

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 01, 2023

The c.589G>A (p.G197R) alteration is located in exon 2 (coding exon 2) of the CARD6 gene. This alteration results from a G to A substitution at nucleotide position 589, causing the glycine (G) at amino acid position 197 to be replaced by an arginine (R). 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	Benign	0.13
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.093
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.97	D;.
Vest4		0.34
MutPred		0.38		Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);
MVP		0.66
MPC		0.18
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.28
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-40843559;