17-80203881-G-T

Variant names:

• chr17-80203881-G-T
• rs143600438
• NM_001366385.1:c.2279G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001366385.1(CARD14):​c.2279G>T​(p.Arg760Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,442,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. R760H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CARD14 NM_001366385.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25

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]

ENSG00000262580 (HGNC:):

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.283854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.2279G>T	p.Arg760Leu	missense_variant	Exon 19 of 24	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.2279G>T	p.Arg760Leu	missense_variant	Exon 19 of 24		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442136 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000191 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T;T;T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.58	.;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	.;.;N
REVEL	Benign	0.19
Sift	Benign	0.33	.;.;T
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.19	B;B;B
Vest4		0.53
MutPred		0.41		Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);
MVP		0.65
MPC		0.38
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.16
gMVP		0.34

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: rs143600438; hg19: chr17-78177680;