17-80192527-G-A

Position:

• chr17-80192527-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366385.1(CARD14):​c.1264G>A​(p.Glu422Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,613,618 control chromosomes in the GnomAD database, including 763 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (58 hom., cov: 33)
  • Exomes 𝑓: 0.029 (705 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.19

Genes affected

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033420026).
• BP6: Variant 17-80192527-G-A is Benign according to our data. Variant chr17-80192527-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80192527-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.1264G>A	p.Glu422Lys	missense_variant	12/24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.1264G>A	p.Glu422Lys	missense_variant	12/24		NM_001366385.1	ENSP00000498071	P1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3289 AN: 152210 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0228 AC: 5728 AN: 250914 Hom.: 86 AF XY: 0.0234 AC XY: 3169 AN XY: 135702

Gnomad AFR exome AF: 0.00532

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00840

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0343

GnomAD4 exome AF: 0.0294 AC: 43027 AN: 1461290 Hom.: 705 Cov.: 30 AF XY: 0.0294 AC XY: 21336 AN XY: 726938

Gnomad4 AFR exome AF: 0.00571

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00859

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0334

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0216 AC: 3288 AN: 152328 Hom.: 58 Cov.: 33 AF XY: 0.0202 AC XY: 1502 AN XY: 74496

Gnomad4 AFR AF: 0.00608

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0329

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0312 Hom.: 127

Bravo AF: 0.0216

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0292 AC: 251

ExAC AF: 0.0228 AC: 2768

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0359

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 32199921) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.68	.;.;T;T
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	.;.;.;N
REVEL	Benign	0.033
Sift	Benign	0.10	.;.;.;T
Sift4G	Benign	0.22	T;.;T;T
Polyphen		0.88	P;P;.;P
Vest4		0.12
MPC		0.31
ClinPred		0.0051	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.25

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: rs61751629; hg19: chr17-78166326;