17-80181383-A-C

Variant names:

• chr17-80181383-A-C
• rs9906472
• NM_001366385.1:c.-20-36A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001366385.1(CARD14):​c.-20-36A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 1,495,346 control chromosomes in the GnomAD database, including 224,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.59 (28239 hom., cov: 32)
  • Exomes 𝑓: 0.54 (195943 hom.)
• Consequence: CARD14 NM_001366385.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.239

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 17-80181383-A-C is Benign according to our data. Variant chr17-80181383-A-C is described in ClinVar as [Benign]. Clinvar id is 1260535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARD14	NM_001366385.1	c.-20-36A>C		intron_variant	Intron 4 of 23	ENST00000648509.2	NP_001353314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARD14	ENST00000648509.2	c.-20-36A>C		intron_variant	Intron 4 of 23		NM_001366385.1	ENSP00000498071.1

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90379 AN: 151950 Hom.: 28199 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.536 AC: 719992 AN: 1343278 Hom.: 195943 Cov.: 21 AF XY: 0.537 AC XY: 355163 AN XY: 661014

African (AFR) AF: 0.793 AC: 24211 AN: 30514

American (AMR) AF: 0.363 AC: 12315 AN: 33970

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 13360 AN: 23972

East Asian (EAS) AF: 0.697 AC: 24496 AN: 35162

South Asian (SAS) AF: 0.593 AC: 45558 AN: 76864

European-Finnish (FIN) AF: 0.591 AC: 28378 AN: 48030

Middle Eastern (MID) AF: 0.593 AC: 3146 AN: 5302

European-Non Finnish (NFE) AF: 0.521 AC: 538117 AN: 1033726

Other (OTH) AF: 0.546 AC: 30411 AN: 55738

GnomAD4 genome AF: 0.595 AC: 90471 AN: 152068 Hom.: 28239 Cov.: 32 AF XY: 0.594 AC XY: 44159 AN XY: 74340

African (AFR) AF: 0.780 AC: 32351 AN: 41492

American (AMR) AF: 0.424 AC: 6473 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1921 AN: 3470

East Asian (EAS) AF: 0.652 AC: 3373 AN: 5174

South Asian (SAS) AF: 0.610 AC: 2945 AN: 4828

European-Finnish (FIN) AF: 0.603 AC: 6382 AN: 10576

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35253 AN: 67942

Other (OTH) AF: 0.553 AC: 1163 AN: 2102

Alfa AF: 0.431 Hom.: 1215

Bravo AF: 0.589

Asia WGS AF: 0.621 AC: 2159 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.47
PhyloP100		-0.24
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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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Other links and lift over

dbSNP: rs9906472; hg19: chr17-78155182; COSMIC: COSV107424600; COSMIC: COSV107424600;