5-40843659-G-A

Position:

• chr5-40843659-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032587.4(CARD6):​c.791G>A​(p.Gly264Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,566,530 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (8 hom.)
• Consequence: CARD6 NM_032587.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.681

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026488304).
• BP6: Variant 5-40843659-G-A is Benign according to our data. Variant chr5-40843659-G-A is described in ClinVar as [Benign]. Clinvar id is 714252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00677 (1030/152254) while in subpopulation AFR AF= 0.0221 (920/41548). AF 95% confidence interval is 0.021. There are 8 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD6	NM_032587.4	c.791G>A	p.Gly264Glu	missense_variant	2/3	ENST00000254691.10	NP_115976.2
CARD6	XM_047417836.1	c.-208G>A		5_prime_UTR_variant	1/3		XP_047273792.1
CARD6	XM_017009989.2	c.283+1994G>A		intron_variant			XP_016865478.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD6	ENST00000254691.10	c.791G>A	p.Gly264Glu	missense_variant	2/3	1	NM_032587.4	ENSP00000254691.5
CARD6	ENST00000381677.4	c.791G>A	p.Gly264Glu	missense_variant	2/3	1		ENSP00000371093.3

Frequencies

GnomAD3 genomes AF: 0.00673 AC: 1024 AN: 152136 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00215 AC: 428 AN: 199422 Hom.: 4 AF XY: 0.00155 AC XY: 167 AN XY: 107652

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.000174

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000494

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000812 AC: 1149 AN: 1414276 Hom.: 8 Cov.: 32 AF XY: 0.000683 AC XY: 479 AN XY: 701806

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00677 AC: 1030 AN: 152254 Hom.: 8 Cov.: 33 AF XY: 0.00633 AC XY: 471 AN XY: 74442

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00137 Hom.: 3

Bravo AF: 0.00778

ESP6500AA AF: 0.0195 AC: 86

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00231 AC: 280

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.0
DANN	Benign	0.26
DEOGEN2	Benign	0.00092	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.041
Sift	Benign	0.71	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;.
Vest4		0.041
MVP		0.11
MPC		0.030
ClinPred		0.0050	T
GERP RS		2.7
Varity_R		0.068
gMVP		0.067

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: rs61757657; hg19: chr5-40843761;