Genetic Variant NM_001366385.1:c.2822G>T (chr17-80208152-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001366385.1(CARD14):c.2822G>T(p.Arg941Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R941Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.77

Publications

2 publications found

Variant links:

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 links:

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]

SGSH Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 3A
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, Myriad Women’s Health, G2P

SGSH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38128847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1 link	c.2822G>T	p.Arg941Leu	missense_variant	Exon 24 of 24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2 link	c.2822G>T	p.Arg941Leu	missense_variant	Exon 24 of 24		NM_001366385.1	ENSP00000498071.1		Q9BXL6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1391562

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685254

African (AFR)

AF:

0.00

AC:

AN:

31480

American (AMR)

AF:

0.00

AC:

AN:

35508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25068

East Asian (EAS)

AF:

0.00

AC:

AN:

35578

South Asian (SAS)

AF:

0.00

AC:

AN:

78704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4450

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075082

Other (OTH)

AF:

0.00

AC:

AN:

57578

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

T;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

.;.;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

M;M;M

PhyloP100

1.8

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.0

.;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.010

.;.;D

Sift4G

Benign

0.11

T;.;T

Polyphen

0.99

D;D;D

Vest4

0.20

MutPred

0.44

Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);Loss of MoRF binding (P = 0.0056);

MVP

0.80

MPC

0.70

ClinPred

0.99

GERP RS

3.8

Varity_R

0.58

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over