Genetic Variant NM_001366385.1:c.28G>T (chr17-80181466-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001366385.1(CARD14):c.28G>T(p.Ala10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A10P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CARD14
NM_001366385.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.435

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028411895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1 link	c.28G>T	p.Ala10Ser	missense_variant	Exon 5 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.28G>T	p.Ala10Ser	missense_variant	Exon 5 of 24		NM_001366385.1	ENSP00000498071.1		Q9BXL6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1429948

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708438

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32728

American (AMR)

AF:

0.00

AC:

AN:

40332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25522

East Asian (EAS)

AF:

0.00

AC:

AN:

37990

South Asian (SAS)

AF:

0.00

AC:

AN:

81716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1095944

Other (OTH)

AF:

0.00

AC:

AN:

59218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.021

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.0075

T;T;T;.;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.53

.;.;.;T;T;T

M_CAP

Benign

0.0053

MetaRNN

Benign

0.028

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.23

.;N;N;.;N;N

PhyloP100

-0.43

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.070

.;.;.;.;.;N

REVEL

Benign

0.015

Sift

Benign

0.57

.;.;.;.;.;T

Sift4G

Benign

0.53

T;T;.;T;T;T

Polyphen

0.0010

.;B;B;.;.;B

Vest4

0.027, 0.026

MutPred

0.15

Gain of phosphorylation at A10 (P = 0.0199);Gain of phosphorylation at A10 (P = 0.0199);Gain of phosphorylation at A10 (P = 0.0199);Gain of phosphorylation at A10 (P = 0.0199);Gain of phosphorylation at A10 (P = 0.0199);Gain of phosphorylation at A10 (P = 0.0199);

MVP

0.64

MPC

0.14

ClinPred

0.030

GERP RS

-8.5

Varity_R

0.032

gMVP

0.21

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

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NM_001366385.1:c.28G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over