Genetic Variant NM_001366385.1:c.2279G>A (chr17-80203881-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BS1BS2_Supporting

The NM_001366385.1(CARD14):c.2279G>A(p.Arg760His) variant causes a missense change. The variant allele was found at a frequency of 0.0000332 in 1,594,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R760C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.25

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:

ENSG00000262580 (HGNC:):

ENSG00000262580 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, ClinGen, Myriad Women’s Health, PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

SGSH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12363917).

BP6

Variant 17-80203881-G-A is Benign according to our data. Variant chr17-80203881-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 569055.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000092 (14/152192) while in subpopulation EAS AF = 0.000389 (2/5146). AF 95% confidence interval is 0.000112. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 14 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARD14	NM_001366385.1	MANE Select	c.2279G>A	p.Arg760His	missense	Exon 19 of 24	NP_001353314.1	Q9BXL6-1
CARD14	NM_024110.4		c.2279G>A	p.Arg760His	missense	Exon 16 of 21	NP_077015.2	Q9BXL6-1
CARD14	NR_047566.2		n.2406G>A		non_coding_transcript_exon	Exon 17 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARD14	ENST00000648509.2	MANE Select	c.2279G>A	p.Arg760His	missense	Exon 19 of 24	ENSP00000498071.1	Q9BXL6-1
CARD14	ENST00000344227.6	TSL:1	c.2279G>A	p.Arg760His	missense	Exon 16 of 21	ENSP00000344549.2	Q9BXL6-1
CARD14	ENST00000651672.1		c.2279G>A	p.Arg760His	missense	Exon 18 of 23	ENSP00000499145.1	A0A494C1N2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000510

AC:

AN:

215708

AF XY:

0.0000346

show subpopulations

Gnomad AFR exome

AF:

0.000300

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000181

Gnomad FIN exome

AF:

0.0000545

Gnomad NFE exome

AF:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1442132

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

715216

show subpopulations

African (AFR)

AF:

0.000390

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

41808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25486

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39162

South Asian (SAS)

AF:

0.0000364

AC:

AN:

82382

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51444

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1103162

Other (OTH)

AF:

0.0000502

AC:

AN:

59740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000389

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000581

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Pityriasis rubra pilaris;C1864497:Psoriasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.59

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

4.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

REVEL

Benign

0.15

Sift

Benign

0.079

Sift4G

Pathogenic

0.0

Polyphen

0.78

Vest4

0.33

MVP

0.74

MPC

0.21

ClinPred

0.11

GERP RS

4.1

Varity_R

0.079

gMVP

0.27

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over