chr5-40852362-A-G

Position:

• chr5-40852362-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032587.4(CARD6):​c.1030A>G​(p.Ile344Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CARD6 NM_032587.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0980

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027489811).
• BP6: Variant 5-40852362-A-G is Benign according to our data. Variant chr5-40852362-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2338815.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD6	NM_032587.4	c.1030A>G	p.Ile344Val	missense_variant	3/3	ENST00000254691.10	NP_115976.2
CARD6	XM_017009989.2	c.472A>G	p.Ile158Val	missense_variant	2/2		XP_016865478.1
CARD6	XM_047417836.1	c.148A>G	p.Ile50Val	missense_variant	3/3		XP_047273792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD6	ENST00000254691.10	c.1030A>G	p.Ile344Val	missense_variant	3/3	1	NM_032587.4	ENSP00000254691.5
CARD6	ENST00000381677.4	c.842-7636A>G		intron_variant		1		ENSP00000371093.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.013
DANN	Benign	0.25
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.75	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0060
Sift	Benign	0.43	T
Sift4G	Benign	0.99	T
Polyphen		0.0050	B
Vest4		0.045
MutPred		0.22		Gain of disorder (P = 0.1028);
MVP		0.092
MPC		0.025
ClinPred		0.027	T
GERP RS		-8.8
Varity_R		0.014
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs957621194; hg19: chr5-40852464;