17-80198145-G-C

Variant names:

• chr17-80198145-G-C
• rs2066964
• NM_001366385.1:c.1641G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366385.1(CARD14):​c.1641G>C​(p.Arg547Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,612,916 control chromosomes in the GnomAD database, including 116,819 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R547R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10054 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106765 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0340
• Publications: 42 publications found

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]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0025016E-4).
• BP6: Variant 17-80198145-G-C is Benign according to our data. Variant chr17-80198145-G-C is described in ClinVar as Benign. ClinVar VariationId is 402485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366385.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	NM_001366385.1	MANE Select	c.1641G>C	p.Arg547Ser	missense	Exon 15 of 24	NP_001353314.1	Q9BXL6-1
	CARD14	NM_024110.4		c.1641G>C	p.Arg547Ser	missense	Exon 12 of 21	NP_077015.2	Q9BXL6-1
	CARD14	NM_001257970.1		c.1641G>C	p.Arg547Ser	missense	Exon 12 of 15	NP_001244899.1	Q9BXL6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARD14	ENST00000648509.2	MANE Select	c.1641G>C	p.Arg547Ser	missense	Exon 15 of 24	ENSP00000498071.1	Q9BXL6-1
	CARD14	ENST00000344227.6	TSL:1	c.1641G>C	p.Arg547Ser	missense	Exon 12 of 21	ENSP00000344549.2	Q9BXL6-1
	CARD14	ENST00000570421.5	TSL:1	c.1641G>C	p.Arg547Ser	missense	Exon 12 of 15	ENSP00000461806.1	Q9BXL6-2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54625 AN: 151870 Hom.: 10051 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.357

GnomAD2 exomes AF: 0.372 AC: 93363 AN: 251266 AF XY: 0.382

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.498

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.379 AC: 553711 AN: 1460928 Hom.: 106765 Cov.: 40 AF XY: 0.383 AC XY: 278453 AN XY: 726792

African (AFR) AF: 0.319 AC: 10654 AN: 33430

American (AMR) AF: 0.236 AC: 10548 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12950 AN: 26092

East Asian (EAS) AF: 0.510 AC: 20258 AN: 39688

South Asian (SAS) AF: 0.443 AC: 38158 AN: 86228

European-Finnish (FIN) AF: 0.380 AC: 20187 AN: 53186

Middle Eastern (MID) AF: 0.514 AC: 2942 AN: 5724

European-Non Finnish (NFE) AF: 0.373 AC: 414887 AN: 1111500

Other (OTH) AF: 0.383 AC: 23127 AN: 60366

GnomAD4 genome AF: 0.360 AC: 54644 AN: 151988 Hom.: 10054 Cov.: 32 AF XY: 0.358 AC XY: 26593 AN XY: 74282

African (AFR) AF: 0.315 AC: 13058 AN: 41476

American (AMR) AF: 0.302 AC: 4612 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1745 AN: 3428

East Asian (EAS) AF: 0.466 AC: 2405 AN: 5160

South Asian (SAS) AF: 0.431 AC: 2078 AN: 4822

European-Finnish (FIN) AF: 0.380 AC: 4024 AN: 10586

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25469 AN: 67940

Other (OTH) AF: 0.361 AC: 760 AN: 2108

Alfa AF: 0.385 Hom.: 8667

Bravo AF: 0.350

TwinsUK AF: 0.382 AC: 1418

ALSPAC AF: 0.372 AC: 1435

ESP6500AA AF: 0.313 AC: 1379

ESP6500EA AF: 0.383 AC: 3292

ExAC AF: 0.377 AC: 45771

Asia WGS AF: 0.434 AC: 1511 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.395

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Pityriasis rubra pilaris (1)
-	-	1	Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)
-	-	1	Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.6
DANN	Benign	0.64
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.034
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.019
Sift	Benign	0.59	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.31		Gain of phosphorylation at R547 (P = 0.017)
MPC		0.17
ClinPred		0.0040	T
GERP RS		0.71
Varity_R		0.074
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2066964; hg19: chr17-78171944; COSMIC: COSV60123851; COSMIC: COSV60123851;