rs34850974

chr17-80208215-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.2885G>A(p.Arg962Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,559,890 control chromosomes in the GnomAD database, including 884 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. R962W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (491 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (393 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.740

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]

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011251271).
• BP6: Variant 17-80208215-G-A is Benign according to our data. Variant chr17-80208215-G-A is described in ClinVar as [Benign]. Clinvar id is 458102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80208215-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARD14	NM_001366385.1	c.2885G>A	p.Arg962Gln	missense_variant	24/24	ENST00000648509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARD14	ENST00000648509.2	c.2885G>A	p.Arg962Gln	missense_variant	24/24		NM_001366385.1	P1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6432 AN: 152160 Hom.: 489 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0103 AC: 1738 AN: 168668 Hom.: 114 AF XY: 0.00783 AC XY: 700 AN XY: 89386

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.00684

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00439

GnomAD4 exome AF: 0.00431 AC: 6061 AN: 1407612 Hom.: 393 Cov.: 32 AF XY: 0.00368 AC XY: 2560 AN XY: 694964

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.00790

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.000300

Gnomad4 FIN exome AF: 0.0000205

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.00944

GnomAD4 genome AF: 0.0423 AC: 6446 AN: 152278 Hom.: 491 Cov.: 33 AF XY: 0.0414 AC XY: 3080 AN XY: 74462

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0123 Hom.: 90

Bravo AF: 0.0474

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.139 AC: 603

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.0103 AC: 1192

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.47
Dann	Benign	0.81
DEOGEN2	Benign	0.012	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0089	N
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.15	T;.;T
Polyphen		0.0	B;B;B
Vest4		0.067
MPC		0.17
ClinPred		0.0022	T
GERP RS		-7.3
Varity_R		0.022
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs34850974; hg19: chr17-78182014;