5-40852373-C-G

Position:

• chr5-40852373-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032587.4(CARD6):​c.1041C>G​(p.His347Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CARD6 NM_032587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.486

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061525762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD6	NM_032587.4	c.1041C>G	p.His347Gln	missense_variant	3/3	ENST00000254691.10	NP_115976.2
CARD6	XM_017009989.2	c.483C>G	p.His161Gln	missense_variant	2/2		XP_016865478.1
CARD6	XM_047417836.1	c.159C>G	p.His53Gln	missense_variant	3/3		XP_047273792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD6	ENST00000254691.10	c.1041C>G	p.His347Gln	missense_variant	3/3	1	NM_032587.4	ENSP00000254691.5
CARD6	ENST00000381677.4	c.842-7625C>G		intron_variant		1		ENSP00000371093.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jan 30, 2024

The c.1041C>G (p.H347Q) alteration is located in exon 3 (coding exon 3) of the CARD6 gene. This alteration results from a C to G substitution at nucleotide position 1041, causing the histidine (H) at amino acid position 347 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.5
DANN	Benign	0.51
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.095
Sift	Benign	0.27	T
Sift4G	Benign	0.44	T
Polyphen		0.022	B
Vest4		0.036
MutPred		0.25		Loss of helix (P = 0.1299);
MVP		0.45
MPC		0.028
ClinPred		0.026	T
GERP RS		-0.44
Varity_R		0.048
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-40852475;