rs61751630

chr17-80195575-C-T

Variant summary

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

The NM_001366385.1(CARD14):c.1517C>T(p.Pro506Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,612,032 control chromosomes in the GnomAD database, including 273 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P506R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 33)
  • Exomes 𝑓: 0.015 (257 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0430

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=0.0025039911).
• BP6: Variant 17-80195575-C-T is Benign according to our data. Variant chr17-80195575-C-T is described in ClinVar as [Benign]. Clinvar id is 458088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80195575-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0107 (1622/152266) while in subpopulation SAS AF= 0.0455 (219/4812). AF 95% confidence interval is 0.0406. There are 16 homozygotes in gnomad4. There are 763 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.1517C>T	p.Pro506Leu	missense_variant	14/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.1517C>T	p.Pro506Leu	missense_variant	14/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1623 AN: 152148 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0455

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0137 AC: 3365 AN: 245954 Hom.: 64 AF XY: 0.0154 AC XY: 2057 AN XY: 133850

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.00455

Gnomad EAS exome AF: 0.000547

Gnomad SAS exome AF: 0.0475

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0147 AC: 21460 AN: 1459766 Hom.: 257 Cov.: 31 AF XY: 0.0155 AC XY: 11249 AN XY: 726174

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00576

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0441

Gnomad4 FIN exome AF: 0.00624

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0107 AC: 1622 AN: 152266 Hom.: 16 Cov.: 33 AF XY: 0.0102 AC XY: 763 AN XY: 74452

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0455

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0126 Hom.: 20

Bravo AF: 0.00911

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0169 AC: 145

ExAC AF: 0.0144 AC: 1752

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pityriasis rubra pilaris;C1864497:Psoriasis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.73
Dann	Benign	0.63
DEOGEN2	Benign	0.0045	T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0037	N
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.38	T;.;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.034
MPC		0.15
ClinPred		0.0013	T
GERP RS		1.4
Varity_R		0.027
gMVP		0.12

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: rs61751630; hg19: chr17-78169374; COSMIC: COSV60126529;